Adaptive design clinical trials - now comes the FDA's draft guidance

For last several years, 'adaptive design' and 'adaptive clinical trials' are hot topics in biostatistics and clinical trial fields. The industry seems to think that 'adaptive design' is the solution for lengthy and costly drug development program. There are workshops, symposiums, many publications and books about the adaptive design in last several years. However, in reality, many examples, case studies are post hoc and  based on the simulation from the historical non-adaptive clinical trial data ("had we implemented the adaptive design, we would have saved xxx time/cost/sample size..."). Recently we do see some implementation of adaptive designs in real clinical trials, but

these are mainly in early stage studies.

This month, FDA issues its guidance for industry on "adaptive design clinical trials for drugs and biologicals". This lengthy guidance contains plenty of references (perhaps with most references for a FDA guidance). Overall tone of this guidance seems to advise the sponsors be cautious in adopting the adaptive design especially those not well established designs. If you don't want to read the entire guidance, slides by two of the FDA working group members summarize the key points in the guidance.

Ahead of FDA, EU has already issued its guidance on adaptive design (or flexible design) . Their opinions have been laid out in EMEA’s REFLECTION PAPER ON METHODOLOGICAL ISSUES IN CONFIRMATORY CLINICAL TRIALS WITH FLEXIBLE DESIGN AND ANALYSIS PLAN issued in 2006. 

There was also a well publicized workshop on adaptive design in 2006 in US. However, we have to wait for four years to see FDA's draft guidance. For documentation, all materials from 2006 workshop are now on the web.

Some of the topics are on technical sides, but there are also talks about the perspectives from FDA regarding the adaptive designs.

• Dr Robert Temple from FDA regarding “Myth Busting – Clinical”
• Dr Robert O’Neill from FDA regarding “Myth Busting – Statistical”

SAS procedures for group sequential design

Group sequential design has been proposed for a while perhaps since Pocock's paper in 1977. At least for last two decades, the group sequential design and interim analysis have been used in may major clinical trials.

Several years ago, I tried to purchase Cytel's EAST program. But I gave up due to the price and the infrequent use in day-to-day practices.

Now I am pretty happy to know that SAS version 9.2 includes two new procedures for group sequential design. Proc SEQDESIGN allows to calculate the boundaries and Proc SEQTEST allows to perform the tests during the interim analysis whether or not the boundaries have been reached. Proc SEQTEST can also be used to calculate the conditional power (Probability of observing a significant result at full information, given the current data and the specified alternative under the statistical design ) and predictive power.


Reference readings:

• Yang Yuan "Group Seuqential Analysis Using the New SEQDESIGN and SEQTEST procedures"

• Schulz and Grimes (2005) Multiplicity in randomized trials II: subgroup and interim analyses. Lancet

Cholesterol Drug Approved for People Without High Cholesterol

Are you willing to take Statin medication if you have normal or mild elevation of LDL-Cholesterol level, but with elevated CRP?

Last week, FDA approved new indication for Crestor -  one of the Statin class cholesterol lowering drug. This new indication has nothing to do with cholesterol level, but it is based on the CRP (c-reaction protein). Wall Street Jounal Health Blog had an article titled "Cholesterol drug approved for people without high cholesterol". It seems to me that we have now invented another disease - perhpas hyperCRP (instead of hypercholesterolemia). American are now perhaps inventing more diseases/indications than ever before.  In the end, both cholesterol level and CRP level are surrogate endpoint. While the relationship between high cholesterol level and the major cardiovascular events (mortality, MI, stroke,...) has been generally recognized, the relationship between high CRP and the major cardiovascular events mainly relies on one study - JUPITER study -  a study stopped early for efficacy.When the conflict of interest issue is considered, the purpose of the study is questioned and skeptical. According to the web blog, there are two conflict of interest issues in this study: "first, the study was funded by AstraZeneca, maker of the study drug, rosuvastatin (Crestor); second, the first author, Paul Ridker of Harvard, owns a patent on the high-sensitivity test for C-reactive protein, the test that would be widely used if the study results are accepted."

It will be inevitable that the next step for pharmaceutical companies like AstraZeneca is to push for routine testing of CRP (CRP screening) in clinical practice to identify the patients with normal or mild elevated LDL-Cholesterol level, but with elevated CRP. A cut point (or normal range) for CRP will be established. This is just how it works in capitalism world.

To find out how convincing of the evidences from JUPITER trial, you can read the publications by yourself. While the evidences seem to be convincing, I just don't want to take medications just for the elevated CRP. Perhaps, instead of the benefit from taking long-term treatment of Crestor, the treatment effect is really due to the detrimental effect of long-term treatment of Placebo. Perhaps, the treatment effect will be gone if we compare the Crestor with no-treatment (instead of Placebo).

• JUPITER hits New Orleans: landmark study shows statins benefit healthy individuals with high CRP levels
• Rosuvastatin to prevent vascular events in men and women with elevated c-reaction protein
• JUPITER study slides 
• The Jupiter Study, CRP Screening, and Aggressive Statin Therapy-implications for the Primary Prevention of Cardiovascular Disease

Now there is even a study claiming that the Statin prevention in patients with elevated c-reaction protein deems to be cost-effective.

Cost-benefit analysis: put a dollar value on human life?

Putting a Price Tag on Life: Today, companies and governments often use Jeremy Bentham’s utilitarian logic under the name of “cost-benefit analysis.” In Michael Sandel's lecture at Harvard, he presents some contemporary cases in which cost-benefit analysis was used to put a dollar value on human life. The cases give rise to several objections to the utilitarian logic of seeking “the greatest good for the greatest number.” Should we always give more weight to the happiness of a majority, even if the majority is cruel or ignoble? Is it possible to sum up and compare all values using a common measure like money?

 

Ford Pinto Case
One of the examples he used is the cost-benefit analysis in Ford Pinto case. According to Wikipedia,the Ford Pinto model became a focus of a major scandal when it was alleged that the car's design allowed its fuel tank to be easily damaged in the event of a rear-end collision which sometimes resulted in deadly fires and explosions. Critics argued that the vehicle's lack of a true rear bumper as well as any reinforcing structure between the rear panel and the tank meant that in certain collisions, the tank would be thrust forward into the differential, which had a number of protruding bolts that could puncture the tank. This, and the fact that the doors could potentially jam during an accident (due to poor reinforcement)allegedly made the car less safe than its contemporaries.
Ford allegedly was aware of this design flaw but refused to pay for a redesign. Instead, it was argued, Ford decided it would be cheaper to pay off possible lawsuits for resulting deaths. Mother Jones Magazine obtained the cost-benefit analysis that it said Ford had used to compare the cost of an $11 repair against the monetary value of a human life, in what became known as the Ford Pinto memo. The characterization of Ford's design decision as gross disregard for human lives in favor of profits led to significant lawsuits. While Ford was acquitted of criminal charges, it lost several million dollars and gained a reputation for manufacturing "the barbecue that seats four."

 

Repairing the Ford Pinto
Cost of Repairing                           Cost of Not Repairing
$ 11 per part                                 180 deaths x $200,000
x 12.5 million cars                          + 180 injuries x $67,000
                                                    + 2000 vehicles x $700
=====================================================================
$137 million                                   = $49.5 million
 (to improve safety)                          (to let it go) 

 

Philip Morris Czech Republic Cost-Benefit Analysis of Smoking

 

This is rather more recent case. The detail report can be found at this website.

Cost                                             Benefits
Increased Health Care costs          Tax revenue from cigarette sales
(due to lung cancer)                       Health care savings
                                                         (from early deaths)
                                                     Pension savings
                                                     Savings in housing costs

 

Net gain if citizens smoke is $147 million
Saving from premature deaths is $1227.00 per person

 

 

The fundamental issue in both cases is whether or not we can put a dollar value on human life (in the first example, a $200,000 tag for each death; in the second example, early death from smoking to benefit the government or other people).

 

We can easily see what is wrong and what is right in  both of these examples. However, in our real life, it is not easy to distinguish the right and the wrong.

 

In UK, a famous government agency is called The National Institute for Health and Clinical Excellence (NICE). NICE's main function is to provide the appraisals that are based primarily on evaluations of efficacy and cost-effectiveness. They actually put a monetory tag on human life (not for each death, but for a good-quality year). The cost-effectiveness limit (or threshold) for NICE is £30,000 per good-quality year of life gained. In many occasions, the novice drug could be denied if the drug is too expensive (over the limit of the price tag). NICE is not nice to the pharmaceutical companies.

If we can not put a price tag on human life, can we put a price tag on 3 months or 6 months of human life? If we can not put a price tag on 3 months or 6 months of human life (saved) and curb the use of extremely expensive drug, how the medical cost will be controlled? I don't think there is an easy solution.

Further readings: 

• Smoking is cost-effective, says report
• Doctor's Fury as NICE bans heart drug that could help 40,000 patients
• U.K. Says Tykerb Isn’t Worth Cost, Even With 12 Free Weeks
• UK Says Kidney Cancer Drugs Aren’t Worth the Cost