Context Matters

, oncologist Dr. Ethan Basch talks about his perspective that patient-reported outcomes (PROs) are not widely used in the development process for cancer drugs because they are not often measured in clinical trials.

Though this assessment is generally accepted, we questioned to what extent there is a lack of PRO data in oncology trials.

When analyzing both regulatory approval and global reimbursement decisions, Context Matters tracks PROs (along with many other outcomes and endpoints). So we were curious to take a look inside our database to see what the numbers said about the prevalence of PRO use in oncology.

Dr. Basch specifically points out that PROs are missing from U.S. labels and from published reports of clinical trials. When we looked at clinical trials cited in health technology assessments (HTAs) around the world, we got a different story. In seven solid tumor oncology diseases, 44% of the clinical trials cited in those reports included PROs.	

In addition, Dr. Basch stated that preapproval trials for patients rarely measure symptoms or functional status (even when PRO data is used). We found that symptoms and functional status are the most commonly evaluated PROs. In fact, the PRO instrument cited most frequently in the HTA reports was the Functional Assessment of Cancer Therapy (FACT), an internationally recognized and validated questionnaire that has both general and cancer-specific subscales. FACT addresses physical well-being (energy, pain, nausea, feeling ill, and amount of time spent in bed), social/family well-being, emotional well-being, and functional well-being (working, sleeping, and quality of life).

Although we see the glass as being half full when we examine the frequency and nature of PROs in oncology, Dr. Bausch does make an interesting point that regulators and the pharmaceutical industry prioritize survival-based end points over patient-experience end points. This is consistent with our data, which shows that overall survival and progression-free survival are most often the primary outcomes of clinical trials. So while we may disagree with his assessment of low PRO use as evidence, we do think that Dr. Basch has raised several interesting questions for consideration.

PRO data is being measured and does exist, but it seems that PROs are not being weighed strongly in regulatory and reimbursement decision-making. In an environment that is increasingly focused on how best to incorporate patient-centered evidence, we find that this seeming disconnect may be an opportunity to explore a potential bias against PROs.

Does the hierarchy of evidence not address the role of PROs?

 How should PROs be weighted among the endpoints captured in clinical trials?

 What is the appropriate role of PROs in oncology?

 While we applaud Dr. Basch’s focus on the role of PROs in oncology, we believe that the real issue at hand is not about the lack of PROs or the lack of measurement of patient experience. The more interesting question and concern should be how (and how much) should PROs and patient-centered experiences be included in any overall assessment of oncology drug efficacy and effectiveness.

Articles

In a recent piece published in the New England Journal of Medicine, oncologist Dr. Ethan Basch talks about his perspective that patient-reported outcomes (PROs) are not widely used in the development process for cancer drugs because they are not often measured in clinical trials.

Patient-Reported Outcomes in Oncology: If No One Pays Attention to Data, Does it Really Exist?

 reported on the recommendation by a group at the National Cancer Institute to change both the definition of cancer as well as treatment and detection techniques.

 as “The uncontrolled growth of abnormal cells in the body,” and modern science has unearthed more than 100 different types of cancer – all with varying degrees of severity and aggression. Dr. Otis W. Brawley, the Chief Medical Officer for the American Cancer Society, notes the need for a more modern definition of cancer which incorporates this new knowledge into practice, “We need a 21st century definition of cancer instead of a 19th century definition of cancer, which is what we’ve been using.”

Reshaping the definition of oncology to be more restrictive is intended to ensure that paths of treatment (which are often painful and expensive) are only used in cases where it is definitively medically warranted – improving patient quality of life as well as saving time, money, and precious medical resources. The clinical side of this recommendation has (justifiably) received the most attention. However, there are broader implications that should not be overlooked.

At Context Matters, we think a stricter definition of what constitutes cancer may have important and, perhaps, unexpected ramifications for drug development. Both regulatory and reimbursement decisions could be changed. Restricting the definition of cancer would affect prevalence and, consequently, drug cost-effectiveness and orphan drug status.

An orphan drug is defined as a treatment for a rare disease. The threshold for what constitutes sufficient “rareness” varies by geography, but all definitions cite prevalence as a key driver – the number of instances of the disease within a particular geography. The Food and Drug Administration (FDA) defines an orphan disease primarily as one that domestically affects fewer than 200,000 individuals. For many years, companies did not rush to develop drugs within orphan disease categories, as their ability to profit was limited from the outset by the rare nature of these disorders.

However, the 1983 Orphan Drug Act corrected this public health imbalance by creating market incentives for orphan drug development through the provision of tax incentives and a more protected patent – in return for the development of an orphan drug.

Consider the above points in the context of a shifting and more restrictive definition of oncology. As what constitutes cancer becomes more limited, certain oncology conditions could fall below the prevalence threshold, allowing treatments for these conditions to apply for orphan designation. Given the tax incentives and enhanced exclusivity protections granted by the FDA, the production of a newly-minted orphan oncology drug could be a real opportunity for both biotechnology and pharmaceutical companies. In light of a potentially narrowing definition of cancer, we believe that new opportunities to obtain orphan status could be created.

We greatly applaud the rationale behind adopting a more restrictive definition of cancer from a clinical care perspective. At the same time, we recognize that the impact of such a change would likely provide opportunities for new drugs to be developed. Testicular cancer is one such cancer where 

prevalence sits near the patient threshold

*. If the definition of cancer becomes even slightly more restrictive, this prevalence number could dip below the requisite threshold for orphan designation; consequently, testicular cancer drugs could soon reap the benefits of orphan protection.

http://seer.cancer.gov/statfacts/html/testis.html

A recent NY Times piece by Tara Parker-Pope reported on the recommendation by a group at the National Cancer Institute to change both the definition of cancer as well as treatment and detection techniques.

Redefining Cancer May Change the Orphan Status of Cancer Drugs

Physicians are increasingly advocating a patient-centered approach to practicing medicine, and both regulatory agencies and manufacturers also seem to agree that patient reported outcomes (PROs) are valuable. Considering this increasing industry-wide interest, you would expect that PROs are increasingly being used across various aspects of drug development - in clinical trials, regulatory reviews, and reimbursement assessments.

At the 17th Annual International Meeting of the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) we presented 

the results of research examining the use of PROs in HTAs

. That study examined 324 reviews published by nine agencies from 2005-2011 for 13 disease conditions.

We thought it would be interesting to revisit this question as our application now has many more reviews available for analysis than in 2012. For the updated analysis, we examined 1,567 reviews. This allowed us to compare the behavior of 12 regulatory agencies worldwide from 2005 to 2012 across 44 disease conditions. Of these reviews 1,394 allowed us to determine definitively whether or not they used PROs. In our update, we restricted consideration to this set of reviews.

Our results were generally consistent with our earlier findings.

Patient reported outcomes were used in 51% of HTAs from 2005 through 2012. They were not used in 49% of HTAs

 Ten of the agencies compared used PROs in more than 50% of their reviews. Three agencies used PROs in more than 80% of their reviews

 Over the eight recent years we examined, there’s no clear trend in PRO use over time. Specifically, the use of PROs in HTAs does not see`m to be increasing

 PROs were used more often in HTAs that resulted in a decision of “Recommend” (62%) than in those resulting in a decision of “Do not recommend” (48%) 

Clearly it’s taking some time for the industry to catch up to what it says it wants to do. It will be interesting to revisit this story again next year to see if 2013 begins to show an upward trend in the use of PROs.

Physicians are increasingly advocating a patient-centered approach to practicing medicine, and both regulatory agencies and manufacturers also seem to agree that patient reported outcomes (PROs) are valuable.

Measuring Up: How Often is PRO Data Being Used in Health Technology Assessments?

A recent Op-Ed piece in the New York Times by Clifton Leaf asked the question “

He covers a lot of ground in his piece, but one thing that caught our attention was his discussion of the use of subgroups by Genentech/Roche in the development of their breast cancer drug Herceptin. Genentech designed the Herceptin trial using representative subgroups of only the types of patients most likely to actually use the drug, were it to be approved.

Leaf applauded this approach and asked why it isn’t used more often. In a broader sense, he questioned the fundamental nature of clinical trial design and the methodology behind them.

We have analyzed the use of subgroups by reimbursement agencies in their health technology assessments (HTAs) – we presented some findings at last year’s 

Canadian Agency for Drugs and Technologies in Health

 (CADTH) Conference – and that work reveals another facet of this issue.

Health Technology Agencies may be unfamiliar to a U.S. audience. Like private payers in the U.S. (insurance companies), these agencies decide which drugs should be recommended for reimbursement in countries with nationalized healthcare.

HTA agencies use clinical trials as evidence in their HTAs. The use of subgroups in clinical trials should be reflected by the use of subgroups in HTAs. Does this imply that if more clinical trials study subpopulations, more HTAs will cite them and if so, will they reach better conclusions?

13 disease conditions
  7 years (2005-2011)
  9 agencies across 7 countries

Only 12% of these HTAs referenced analysis based on subgroups. There was some variation, but the proportion of reviews citing analysis based on subgroups was low among all of the agencies. Interestingly, twice as many (24%) of the reviews mentioned a desire to use subgroup analysis as actually used it. Of course, the true gap between desire and use was likely higher – presumably not all of those reviews that would have used evidence from subpopulations if it had been available revealed that fact.

This gap between the desire to review analysis based on subgroups and actually doing so may be telling. It suggests that there is a shortage of clinical trials using appropriate subgroup analysis.

We compared this 12% rate of use by HTAs to a sample of comparable clinical trials published in top journals. Almost 60% of these clinical trials used some form of subgroup analysis. While our study didn’t match the HTAs to appropriate candidate clinical trials, the large disparity in overall rates suggests that a simple lack of clinical trials using subgroup analysis isn’t the whole reason HTAs so rarely use subpopulations.

The answer probably lies in their need for 

 subpopulation analysis. Other researchers have found that a lot of subpopulation analysis is poorly conceived or executed, and is often misinterpreted. The problem may be less that there is insufficient 

A recent Op-Ed piece in the New York Times by Clifton Leaf asked the question "Do Clinical Trials Work?"

Context Matters

Articles

Patient-Reported Outcomes in Oncology: If No One Pays Attention to Data, Does it Really Exist?

Redefining Cancer May Change the Orphan Status of Cancer Drugs

Measuring Up: How Often is PRO Data Being Used in Health Technology Assessments?

When Does More Subgroup Analysis Equal More Subgroup Analysis?