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HSEM 3708 Spring 2009   Clinical Trials     Assignment 1

Due: February 4, 2009

Answer the following for the paper of Warrell et al. on Dexamethasone for Cerebral
Malaria:

 1.  What was the objective of this study?


 2.  Why was the study being done?  Was there reason to believe that (1) dexamethasone might
     be beneficial, and (2) dexamethasone might be harmful?  What other considerations
     entered into the decision to do the study?


 3.  What population of patients was being studied?


 4.  What was the design of the study?


 5.  What was the primary endpoint?  Why was that an important outcome?


 6.  What test statistics were used to determine if the two groups had different outcomes?


 7.  What were the secondary endpoints?


 8.  What were the main findings of this clinical trial?


 9.  What was the clinical importance of the results of this study?


10.  Were the findings consistently in the same direction for a variety of clinical
     outcome measures?


11.  Is it likely that this study changed clinical practice?  How might you find out?


12.  Why did they randomize 100 patients, rather than, say, 500?


13.  Why did they carry out a randomized clinical trial, rather than just
     observing what happened to patients who were treated at doctors' discretion
     for cerebral malaria?


14.  Is it possible that the findings and recommendations of this study were wrong?
     What would be the consequences if that were true?


15.  Before this study was completed, some people might have said it was unethical
     (see the section on Study Design, p. 314).  How did the investigators address
     that?  


16.  In retrospect, it might seem that it would have been unethical NOT to do
     the study.  What are your thoughts on that?


17.  How was the study funded?  Why might this be relevant?


18.  The investigators don't give exactly the statistics that are necessary to
     compute the p-values that are shown in Figure 1.  They say that the p-value
     comparing the Time to Regain Full Consciousness between the two groups
     is P < 0.02.  See if you can estimate the numbers required to confirm this,
     and describe what you find (see notes001).


19.  Similarly, compute the p-value for comparing the number of patients with
     convulsions between the two groups (Table 2).


20.  Do you have any other comments on this clinical trial?


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Homework #2 - due February 11, 2009

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HSEM 3708 Spring 2009   Clinical Trials     Assignment 2

Due: February 11, 2009

Answer the following for the paper of Shlay, Chaloner et al. on Acupuncture 
and Amitriptyline for HIV-Related Peripheral Neuropathy (J. Amer Med Assoc
1998: v. 280, pp 1590-1595).

 1.  What was the medical problem that was being addressed by this study ?


 2.  Were the investigators trying to study two different treatments at the
     same time?  What are advantages of doing this?  Disadvantages?


 3.  Was there good reason to think that either of the two treatments might
     be effective?


 4.  The acupuncture aspect of this trial was 'placebo-controlled'.  Was it
     double-blind?  Single blind?  What are some of the issues about this?


 5.  Some people are already convinced that acupuncture works.  Others are
     convinced that it does not.  What do you think?  If you were already
     convinced one way or the other, would it be ethical for you to conduct
     this clinical trial?


 6.  How do you interpret the confidence intervals given in the 'Results'
     section of the Abstract (p. 1590) ?  Is the evidence for an effect
     stronger for acupuncture or for amitriptyline?


 7.  The investigators randomized 250 patients.  What was their basis for
     doing this?


 8.  At the end of the Statistical Analysis section, the text says "in
     February 1997, the monitoring board recommended closing the study
     because it concluded that the results were definitive for both
     acupuncture and amitriptyline."  What does that mean, "definitive"?


 9.  How did the investigators choose the points at which the acupuncture
     needles were to be inserted?


10.  Why isn't amitriptyline sold over the counter?


11.  State the main conclusions of this trial in your own words.


12.  What do you think the consequences of this trial were for patients and
     for medical practice?


13.  See the Letters to the Editor and the authors' responses.  What issues
     are raised by the letter writers?  Do you agree with what they say?


14.  How might the investigators have decided on a trial design which
     would have addressed the letter writers' concerns?


15.  Do you think the letter writers would have said the same things
     about the acupuncture points if the results had turned out in
     favor of acupuncture?


16.  The 239 patients in the acupuncture part of the study all knew
     they were getting some kind of acupuncture.  That is, among them
     there was really no 'pure control' group of people who didn't get
     any kind of acupuncture.  In actual medical practice, patients
     get either acupuncture treatment which is believed to be effective,
     or none at all - they do not get an acupuncture treatment which
     is NOT believed to be effective.  Do you think the investigators
     should have included a 'pure control' group?


17.  Some people have done studies of acupuncture to relieve pain in
     dogs and horses.  Is it possible to carry out the evaluations
     so as to rule out the possibility that the investigator's bias
     can affect the results?


18.  If you were suffering from peripheral neuropathy, would you
     want to try acupuncture?  In light of this study, should your 
     insurance company or HMO have to pay for it?  Same questions 
     for amitriptyline.


19.  Do you think there are other alternatives to the two treatments 
     tested in this trial?


20.  Do you have any other comments on this clinical trial?



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Homework #3 - due February 18, 2009

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HSEM 3708 Spring 2009   Clinical Trials     Assignment 3

Due: February 18, 2009

Answer the following for the paper of Omenn, Goodman, et al. on effects
of beta carotene and vitamin A on lung cancer and cardiovascular disease
[the CARET study] (N. Engl J. Med (1996) v. 334, pp 1150-1155).  See also:

 http://content.nejm.org/cgi/content/full/334/18/1150?ijkey=d8874d4c161a8af4cb0bc7b983175ae5f5643803

 and 

 http://content.nejm.org/cgi/content/full/335/14/1065

 For a very brief reference on Survival Curves, see:

 http://www.graphpad.com/www/book/survive.htm


 1.  What was the motivation for doing this study [CARET] ?



 2.  What is a case-control study, and how does it differ from a clinical trial?



 3.  What was the design of the CARET study?



 4.  What were the primary endpoints?



 5.  A total of 18,314 people participated in this study.  Why did it have to
     be so large?  What were the eligibility criteria?



 6.  Summarize the main results in your own words.




 7.  Do you find this study convincing?  Why or why not?



 8.  The study was planned to go on until 1997, but it was stopped in
     January of 1996 and the results were published in May, 1996.  Why
     was the study stopped early, and how did the study's Monitoring
     Board make the decision?  Usually, it takes many months to get an
     article published in a medical journal.  Why was this one published
     so quickly?



 9.  Why are Kaplan-Meier curves often used to summarize data from clinical
     trials like this one?  (See Fig. 1).  Why not just present the numbers
     of people who were diagnosed with lung cancer sometime during the study
     in each of the treatment groups?  What does the Kaplan-Meier graphical 
     presentation add?



10.  There have been some related clinical trials.  You can find them by doing
     searches in Google, using terms like "beta carotene" "lung cancer", etc.
     Briefly summarize the relevant results of these, particularly the Physicians
     Health Study and the ATBC study.




11.  The CARET study and the ATBC study did not agree with previous other studies
     which were not clinical trials.  What are some possible explanations?  Why
     are randomized clinical trials considered the 'Gold Standard' for medical studies?




12.  These studies all involved people at risk for lung cancer (especially,
     smokers).  Do you think the same kind of effects of carotenoids might be
     seen in nonsmokers?  Do you think the effects are confined only to
     lung cancer?  Why or why not?



13.  Not many women were included in these studies.  Why might that have
     been a serious omission?




14.  Do you think it would be ethical now to do another large study of beta
     carotene to see if it might prevent cancer?  In what circumstances?




15.  What does 'antioxidant' mean?  Why do some people think antioxidants are good?





16.  Health food stores sell beta carotene.  Do you think they should?  Should
     they include warning labels for smokers?  Do they?  Do you think the health-
     food store owners and clerks are aware of the CARET and ATBC studies?  
     Should the Food and Drug Administration regulate the sale of beta carotene?
     Should the government actively protect you from behavior that might be
     deemed risky, or just inform you about it, or just not say anything and let 
     you choose to do whatever you want?



17.  Would you take a beta carotene supplement?  Why or why not?  If you were
     randomized into a beta carotene clinical trial, would you try to find out
     whether you were assigned to beta carotene or placebo?  What would you do
     if you knew?



18.  Who funded this study?  I don't know exactly what was the cost of the
     study, but it was likely in the $50M - $100M range.  Did the results justify
     that kind of expense?



19.  Is it likely that this study would have been funded by a drug company?  Why
     or why not?



20.  Other comments on any of this?



21.  Special Assignment for 5 students (to be selected):  Go to a health food
     store and find out what they say about beta carotene, antioxidants, etc.  
     Is the staff aware of the clinical trial reports?  [Try not to be judgemental in
     talking to them - concentrate on just obtaining information]  Write a brief
     report and present your findings to the class.




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Homework #4 - due February 25 2009

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HSEM 3708 Spring 2009   Clinical Trials     Assignment 4

Due: February 25, 2009

Answer the following for the paper of the SMART Study Group:
CD4+ Count-Guided Interrpution of Antiretroviral Treatment
(N. Engl J. Med (2006) v. 355, pp 2283-2296).  See also the
Editorial, NEJM (2006) v. 355, pp 2359-2361.

Web link to the paper:     http://content.nejm.org/cgi/content/short/355/22/2283
Web link to the editorial: http://content.nejm.org/cgi/content/short/355/22/2359


 1.  What was the motivation for doing this clinical trial?



 2.  What was the design?



 3.  What patients were eligible for this trial?



 4.  Why is the CD4+ cell count important?



 5.  What was the primary endpoint ?  What was the alternative hypothesis ?



 6.  The sample size target for the trial was 6000 patients.
     What was the basis for that?



 7.  In the Statistics section of the Methods, it says:
     "Randomization was stratified according to clinical site
     with the use of permuted blocks of random sizes."  What does
     this mean, and why did they do it?  How many clinical sites
     were there?  Where were they?



 8.  The Data and Safety Monitoring Board terminated this trial
     early.  What factors went into their decision?  What is your
     understanding of the "O'Brien-Fleming boundary and the Lan-
     DeMets spending function" ?



 9.  Do you agree with the DSMB's decision to stop early ?  Why or
     why not?  What are some reasons that might be considered to
     continue the study longer?



10.  What does Figure 2 tell you?  What does 'censored observation'
     mean?



11.  What does Figure 3 tell you?



12.  Do you find the results of this trial convincing?  Explain.



13.  Do you think it is likely that the results of this trial will change
     clinical practice?



14.  Some people were disappointed with the results of this study.
     Who were those people, and why were they disappointed?



15.  Who sponsored this study?  Why?




16.  Has there been much improvement in the treatment of HIV/AIDS
     since the disease emerged in the early 1980s?



17.  Does the 'profit motive' play a role in medical progress?  Explain.



18.  Why is HIV/AIDS difficult to prevent and treat?  Why isn't
     there a vaccine?



19,  What are the major points made in the Editorial ?




20.  HIV/AIDS is largely preventable by behavior modification.
     Some people argue that individuals should be responsible for the
     consequences of their own behavior.  Others argue that the
     government should shift its resources more toward prevention rather 
     than treatment.  Others argue that studies like this should be
     done by drug companies, not by the government.  What are your views?




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Homework #5 - due March 4, 2009
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HSEM 3708 Spring 2009   Clinical Trials     Assignment 5

Due: March 4, 2009

This assignment is based on the 'lumpectomy' clinical trial (NEJM, 1985) and
the occurrences of data falsification that occurred in that trial and the
consequences.  Relevant papers include:

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1.  Fisher F, Bauer M, Margolese R, Poisson R et al.  Five-year results of a
    randomized clinical trial comparing total mastectomy and segmental mastectomy
    with or without radiation in the treatment of breast cancer.  NEJM (1985)
    vol 312, pp 665-673.

2.  Angell M, Kassirer J.  Setting the record straight in the breast-cancer trials.
    NEJM (1994) vol 330, pp. 1448-1450 (Editorial).

3.  Peto R, Collins R, Sackett D et al.  The trials of Dr. Bernard Fisher: A
    European perspective on an American Episode.  Controlled Clinical Trials (1997),
    vol 18, pp 1-13.

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Questions:

 1.  What were the reasons for conducting the 'lumpectomy' clinical trial?



 2.  What was the design of the trial ?  What were the primary endpoints?



 3.  Describe eligibility requirements for the trial.  Why were patients with more
     advanced (that is, worse than Stage 2) breast cancer not included ?



 4.  A total of 2263 patients were randomized.  But the 1985 paper reports on only
     1843 of these.  What happened to the others?  Is this a possible weakness of
     the study?  How might the investigators have avoided this situation?


 5.  Note that some of the patients who were assigned to segmental mastectomy and
     had that operation went on later to have total mastectomy (see first paragraph
     under Results).  Should those patients have been excluded from the analysis?
     What effect could including them have on the final results?



 6.  What were the main conclusions of the study?



 7.  Did this clinical trial have an effect on treatment for breast cancer?



 8.  See Figure 1.  Note that the number of patients who had follow-up out to
     5 years was 62 in the SM group and 76 in the SM + RTx group.  These are
     rather small numbers, compared to, e.g., the number of patients who had
     two years of follow-up.  What implication does this have for the certainty
     of the estimate of tumor-free survival at 5 years?




 9.  The last paragraph in the paper speaks of 'a satisfactory cosmetic result'.
     Do you think that a 'satisfactory cosmetic result' was an important goal of
     the investigators?  What is your view?




10.  Do you have other comments on the 1985 paper?




11.  What happened in Pittsburgh in 1990 which caused accusations of fraud later?




12.  What happened between 1990 and 1994 related to the fraud accusations?




13.  Summarize the main points made by Drs. Angell and Kassirer in their 1994
     editorial in NEJM.




14.  Who was to blame, and for what?




15.  How did Dr. Roger Poisson explain his actions?




16.  What happened to Dr. Fisher as a result of this incident?  Dr. Carol Redmond
     was the director of the Data Coordinating Center for the NSABP.  What happened
     to her?  What happened to Dr. Poisson?




17.  What were the long-term effects of this incident on (1) medical practice,
     (2) patient attitudes toward medicine and science, (3) how clinical trials are
     conducted, and (4) NIH policies ?




18.  Summarize the main points of the article by Richard Peto and others in
     the journal Controlled Clinical Trials.




19.  Do you think Drs. Fisher, Redmond and Poisson were treated fairly in this
     incident?




20.  What could have been done to reduce the chances of something like this
     happening again?



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Homework #6 - due March 9, 2009
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HSEM 3708 Spring 2009   Clinical Trials     Assignment 6

Due: March 9, 2009

This assignment is based on a case-control study:

Connett J, Kuller L, Kjelsberg M, Polk B, Collins G, Rider A, Hulley S.
The relationship between beta carotenoids and cancer.  Cancer 64: 126-134, 1989.

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Questions:

 1.  What is a 'case control study' ?



 2.  How does a case-control study differ from a clinical trial?



 3.  This case-control has been described as 'a case control study nested within a
     clinical trial'.  What does that mean?



 4.  What was done early in the MRFIT project which made it possible to do this
     nested case-control study?  Do you think this specific study was planned in advance?




 5.  What was the primary question of interest in this study?




 6.  Describe the design of this case control study.  Specify: how many controls for
     each case; what was the definition of 'case'; what was the definition of 'control';
     what was the length of follow-up.




 7.  What are some advantages of case-control studies versus randomized clinical trials?  Describe
     at least 4.




 8.  What are some disadvantages of case-control studies versus clinical trials?  Are there
     clinical questions for which it would be ethical to carry out a case-control study
     but not ethical to do a randomized clinical trial?  If yes, describe.




 9.  Which is more convincing: a case-control study or a randomized clinical trial?





10.  What were the main findings of this case-control study?




11.  Speculate on what the effects of this case-control study might have been.




12.  What reasons might you give for the disagreement of the results of this case-control
     study versus the CARET and ABC clinical trials?




13.  It is said that if, in a case-control study, you match the cases and controls on
     a given factor (for example, require that cases and controls are matched on gender),
     then you will not be able to study the effects of that factor when
     you obtain the data.  Explain this.




14.  Can you think of an important clinical question which you believe could be
     addressed by a case-control study?  [don't answer 'No'].  Describe a proposed
     study.  How would you match the cases to the controls?  How might it produce 
     misleading results?



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Homework #X - due
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HSEM 3708 Spring 2009   Clinical Trials     Assignment 6

Due:

Write a book review of the book: Deadly Medicine, by Thomas Moore.  The
review should be 3 or more pages double-spaced.  The review should include
answers to the following questions, but should not be rigidly structured
around this list of questions.  Write the review as if you thought it
might get published in a newspaper.

1.  What is this book about?  What is the underlying medical problem?


2.  There are a number of 'stakeholders' (that is, people who are involved or have
    concerns or interests) in the events described in this book.
    What are the major groups of stakeholders, and what is the nature of their
    their interests (e.g., financial, clinical, scientific, other) ?


3.  The book's back cover says that it "tells the story of America's worst
    medical drug disaster".  It goes on to say that an estimated 50,000 people
    died from taking the drugs that are described in the book.
    Do you think this description is an exaggeration?


4.  Had you heard about this 'drug disaster' before reading this book?  Had you heard
    about Three-Mile Island?  How many people died as a result of the Three-
    Mile Island incident?


5.  Summarize the main events described in the book, with a timeline.



6.  What are your views regarding the actions of the following people or
    organizations:

    -  3M Inc.

    -  Joel Morganroth

    -  Robert Temple and the FDA

    -  J. Thomas Bigger, Jr.

    -  Curt Furberg

    -  Lawrence Friedman

    -  Al Hallstrom

    -  Claude Lenfant

    -  Bristol-Meyers and Boehringer-Ingelheim



 7.  What was the CAPS clinical trial?


 8.  What was the CAST clinical trial?  Describe the design, primary endpoint,
     and outcome.  Why was it stopped early?  You may want to refer to the
     CAST primary paper:  NEJM 321, pp. 406-412, 1989 (will be posted on the
     class website).  Who sponsored CAST, and what did it cost?


 9.  Briefly describe CAST II.


10.  What actions were taken by (1) NIH, (2) drug companies, and (3) FDA
     when the results of the first CAST study became known?


11.  Are the drugs that were implicated in patient deaths (Tambocor or
     flecainide acetate; Enkaid or encainide) still being sold and prescribed?


12.  What is meant by the term 'surrogate endpoint' ?


13.  If the author is right, there was something very wrong with the drug
     approval process.  What mistakes may have been made in the testing
     of these antiarrhythmic drugs prior to the FDA giving its approval?



14.  A scandal is frequently a reason for reforms to occur.  Were reforms
     instituted as a result of the events described in this book?  What
     were they?  What reforms might YOU suggest which were not carried out?


15.  Some people have argued that the FDA's drug approval process, and especially
     the requirements to carry out large randomized clinical trials, should be
     relaxed.  They (especially conservative media elements like the Wall
     Street Journal) have argued in favor of not doing randomized clinical trials,
     but instead carrying out nonrandomized studies with "historical controls".
     Others have argued that the drug approval process takes too long and costs
     too much money.

     What are your views on this ?

16.  Speculate on motivations of the drug companies in this controversy:
     It appears that they wanted to continue selling the drugs even after the 
     CAST study was completed.  Were they evil people with evil intentions?  Did 
     they not want to 'lose face' after claiming that their drugs were safe?  Were
     they determined to make a profit at all costs?  How did they rationalize
     away the findings?

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Most recent update: January 25, 2009.