Shilpa Viswanathan

Top Related Articles: Two Decades of Change for PROs

Putting the "e" in FDA's Draft PRO Guidance 

 The growing need to establish a drug's safety and long-term efficacy in a given population has increased the number of late-phase studies performed by the pharmaceutical industry over the past decade. The competitive drug market has driven companies toward product differentiation and positioning, both of which may be determined through postmarketing studies. Strategic guidance in areas such as reimbursement, franchise development, and marketing is provided through late-phase studies.

PHOTOGRAPHY: WESTEND61, PHOTOALTO/ERIC AUDRAS, GETTY IMAGES    ILLUSTRATION: PAUL A. BELCI 

Late-phase trials are postmarketing studies and classified as Phase IIIb or IV. The term Phase IIIb is used by the industry to describe additional therapeutic exploratory and confirmatory studies conducted after the primary regulatory dossier has been submitted by the manufacturer. They are typically conducted on marketed drugs to look for a new indication. Ziprasidone hydrochloride (Geodon), a commonly used antipsychotic introduced to the market for the treatment of schizophrenia in February 2001, received approval for treatment of bipolar mania in August 2004 as a result of Phase IIIb research.

Phase IV studies are typically conducted to capture physician prescription patterns, evaluate adherence to treatment guidelines, and conduct safety surveillance after the approval of a drug. Phase IV postmarketing research has evolved into patient registries, risk management programs, postmarketing surveillance programs, observational studies, disease management programs, and care quality improvement initiatives.

  The Phase IV research environment is largely driven by the changing regulatory environment, increasing safety concerns of new medicines, and the need for real-world data on the marketed drugs' safety and efficacy.

  The association between long-term combination Hormone Replacement Therapy use and a heightened risk of breast cancer was discovered during a Phase IV trial partially funded by Wyeth and conducted by the National Institutes of Health.      

Figure 1. Some of the main factors that lead to treatment ineffectiveness. 

Decision-making by health care professionals in the United States is primarily based on patient visits, is highly decentralized, and driven by professional autonomy to a large extent.

  The prevailing model of health care delivery is complicated, comprised of layers of processes and handoffs that result in slow and expensive health care. The system often fails to consider the importance of tailoring care based on patients' needs. While health care delivery needs to be timely and safe, the overall effectiveness of treatment can be optimized through patient-level feedback. 

Some of the main causes for treatment ineffectiveness have been described in Figure 1. Patient noncompliance, driven in part by lowered treatment satisfaction, has emerged as one of the leading causes for treatment inefficacy. High patient noncompliance leads to annual economic losses of up to $100 billion in the United States. Studies have shown that noncompliance causes 125,000 U.S. deaths annually, and hospital costs due to noncompliance have been estimated to be $8.5 billion annually.

Since the 1990s, studies have shown that systematic attention to patient feedback on health care outcomes and behavioral change lead to improved treatment outcomes.

  According to an IBM publication on health care in the 21st century,

  a patient-centric approach would ensure an improvement in health; a reduction in costs and premiums by payers; improvements in the efficiency, quality, and safety of care; and a reduction of the financial burden in the industry.  

Outcomes that matter to patients following treatment can be gauged most accurately using patient-reported outcomes (PRO) measures. The term PROs has evolved to include any endpoint derived from patient reports, whether collected in the clinic, using a diary or by other means, including single-item outcome measures, event logs, symptom reports or longer questionnaires. PROs are typically used to measure health-related quality of life (HRQoL), health status, symptoms, adherence, and treatment satisfaction.

 The selection of appropriate PRO instruments depends on the study design, nature of the intervention, and the target population. 

Results from psychometrically validated PRO measures can help us learn about overall patient treatment satisfaction, treatment effectiveness, and the impact of the drug on patients' day-to-day lives (see Figure 2). Physicians can gain useful feedback on prescribed treatments and could alter their course of treatment to improve the care delivered. 

The recent FDA and EMEA guidelines providing clarifications on the use of PRO endpoints from clinical trials to support label claims have resulted in a significant increase in the use of PRO measures in clinical studies.

  While PRO measures used in early-phase studies evaluate a drug's safety and efficacy in a small group of patients, PRO measures in late-phase studies are used on a larger patient population and in real-world settings. Compared to the controlled settings used in early-phase studies, the data provided in late-phase research, particularly related to PROs, has better external validity. The observational nature of most late-phase studies requires following patients through their normal course of treatment, which enables better determination of the factors leading to treatment ineffectiveness.  

Figure 2. Mediators contributing to improving treatment effectiveness and safety. 

Since early-phase studies are designed to specifically address drug safety, efficacy, and dose adjustment issues, they do not allow for head-to-head comparisons between drugs. Late-phase studies provide more comprehensive data about overall treatment satisfaction and patient HRQoL in real-world settings (see Table 1). 

A study designed to investigate the scope of HRQoL data from oncology studies showed that more than 80% of oncologists believed that HRQoL information collected prior to the commencement of treatment would improve overall treatment outcomes.

  Health-related quality of life data from late-phase studies can set the stage for physicians to tailor treatment regimens based on patient needs and ensure the provision of timely safe and high-quality health care. 

However, care must be taken to make study design adjustments in the context of observational studies or registries, where patient assessment using a PRO measure has the potential to alter routine clinical care.  

Table 1. Examples of why to use PROs and the different ways the data can be captured. 

Provider attitudes, decision-making, and health care delivery styles can influence treatment outcomes to a great extent. Physician characteristics such as lower practice volume, previous primary care or interviewing training, satisfaction with personal autonomy, and physician specialty are associated with higher doctor/patient participatory decision-making style ratings.

PRO measures from observational studies can provide useful information on the effect of physician attitudes on patient outcomes. Researchers agree that low levels of treatment satisfaction among gastroesophageal reflux disease patients are often a result of inadequate communication between physicians and patients, and believe that an understanding of a patient's HRQoL during the course of the disease would help address this problem.

PRO measures have been used to establish long-term treatment effectiveness and the negative impact of treatment on patients' HRQoL. The Prostate Cancer Outcomes Study (PCOS) was initiated in 1994 in collaboration with six cancer registries that were part of the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Their aim was to obtain information on specific diagnostic procedures, clinical status, and details of treatments using patient surveys, medical records, and registry data.

HRQoL measures such as the SF-36 were used to obtain information on patient treatment satisfaction and disease symptoms. The PCOS generated over 25 publications, and one of the study findings was that with aggressive treatment there was a reduction in absolute risk of dying from prostate cancer but at the cost of a significant decrease in disease-specific HRQoL.

 PRO endpoints in late-phase trials support treatment benefit claims that describe a patient's symptoms or ability to function.

  They can help establish secondary indications for an approved product label. 

Porfimer was approved for a second indication of endobronchial cancer based on two randomized Phase IIIb studies comparing the safety and efficacy of porfimer versus laser therapy alone for the reduction and palliation of symptoms in the patients. Patient symptoms were evaluated using a PRO, the pulmonary symptom severity scale. 

 The most efficacious combination of drugs can often vary among patient populations, and it becomes necessary to conduct the assessment from the patient's perspective, using PRO measures. 

The postmarketing ADORE trial studied the relative efficacy of etanercept alone versus combination therapy of etanercept and methotrexate for patients with rheumatoid arthritis. It established that both treatment options were effective in reducing symptoms associated with rheumatoid arthritis and improving general patient health, by using endpoints from PRO measures like the EQ-5D, the VAS, and the Stanford Health Assessment Questionnaire.

 Treatment modifications, symptom control, and side-effect prevention techniques can be evaluated in late-phase clinical trials using PRO data. 

For example, an open-label observational study used the Short Form-12 (SF-12) to evaluate changes in symptomatology for patients whose antihypertensive drug therapy was modified due to tolerability issues.

  Instruments used in osteoporosis studies, such as the Osteoporosis Functional Disability questionnaire, were developed to assess disability in patients with osteoporosis and back pain due to vertebral fractures. This has led to interventions using fracture prevention techniques in clinical practice.

 PRO-reported side effects can present a comprehensive picture of drug-related safety. Health care researchers use PRO instruments to study side effects in late-phase studies, and experts believe the combined use of side-effect questionnaires with health status instruments could yield a broader understanding of treatment outcomes. 

The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) is comprised of over 1000 individual items related to specific adverse events based on their degree of severity, and has been mandated for identifying toxicity-related symptom burden from chemotherapy patients.

  While the CTCAE was designed for clinician reporting, the rating scale was adapted by researchers for patient self-reporting and to evaluate the efficiency of the electronic collection of PROs.

Online patient reporting was demonstrated to be a feasible strategy for chemotherapy toxicity symptom monitoring, and could improve overall treatment safety and satisfaction with care. Another questionnaire, the Side Effect and Life Satisfaction inventory was useful in the evaluation of side effects among epilepsy patients.

  PRO data in real-world settings assessing side-effects often form the basis for dose modifications or the introduction of supportive medications. 

 Health care researchers and policymakers can use PRO data from late-phase trials to study the burden of disease on the targeted patient population. 

Resource allocation, drug costs, and premium reductions can be made through the extraction of information from postmarketing surveillance data. Using short-term data from the late-phase PROactive trial, a health outcome model was updated to project long-term clinical and cost outcomes associated with pioglitazone versus placebo in patients with type 2 diabetes.

  However, for modeling HRQoL based on Quality-Adjusted Life Years, health state utilities derived from another source was modeled into the event data from the PROactive trial. 

In the future, late-phase studies could incorporate simple preference-based PRO measures such as the EQ-5D to enable researchers to directly obtain information on HRQoL without the need to use multiple data sources. 

While manufacturers and researchers use late-phase clinical trials as instruments to corroborate the safety and long-term effectiveness of their drug, incorporating PRO endpoints could ensure focus on patient-centered health care delivery. PRO data from late-phase trials should percolate through the layers of the health care system to support the industry's growing commitment to patient-centric health care and reinforce the principles of safety, effectiveness, timeliness, efficiency, and equity in health care delivery. 

1. I.F. Moodie, "Emerging Role of Postmarketing Clinical Research," 

Strategic Research: A Practical Handbook for Phase IIIB and Phase IV Clinical Studies

3. D. Polygenis and G. Radulescu, "The Changing Face of Post-Marketing Research," Bioscienceworld, 

http://www.bioscienceworld.ca/TheChangingFaceOfPostMarketingResearch

Articles

Patient-level feedback from later studies provides a multitude of valuable answers to all stakeholders.

Shilpa Viswanathan

Articles

Late Phase Patient Reported Outcomes