Re: Clinical Questions with comments

[Guest guest]

Karl -

1. Are you a CLL patient?

2. Have you volunteered for clinical trials?

3. If so, did the trial(s) benefit you in any way?

4. Were you harmed in any way?

Venkat's recent posting about clinical trials, in which she explores the

role of money and bias in clinical trials, is a useful adjunct to your post.

Adam

>

> Greetings,

>

>

> One of our major goals is to help patients understand the critical role of

clinical trials in making PROGRESS AGAINST LYMPHOMAS / CLL and to provide also

general guidance on when we may reasonably consider clinical trials.

>

>

>

> Please note that not all studies will have a control group and that a placebo

control (i.e., a sugar pill) is never used in oncology trials - the control will

be a standard of care.

>

> =SOME CLINICAL QUESTIONS THAT CAN ONLY BE ANSWERED BY TRIALS:

>

> A. Is this new drug effective when other agents are not?

>

> Comment: Answering this question doesn't require a randomized study if the

refractory status of the patients is well documented. Easiest path to marketing

approval - accelerated / conditional approval.

>

> B. Is protocol A better than protocol B for this type of lymphoma as first

therapy?

>

> Comment: This question is vital to advancing the standard of care †" making

evidence based treatment decisions. It can take a long time to accrue patients

and for data to mature. First treatment could be the best opportunity to cure

lymphomas or induce the most durable remissions which suggest a survival

benefit.

>

> C. Is protocol A better than protocol B for this type of lymphoma at first

relapse?

>

> Comment: Also vital to advancing the standard of care, improving survival and

helping to make evidence-based treatment decisions.

>

> D. Is this protocol curative, and if so does the curative potential outweigh

the risks?

>

> Comment: Takes a very long time for data to mature - up to 12 years for

indolent lymphomas. Historical controls may be sufficient, but studies need to

be large or replicated by independent groups. Patient selection bias is a

problem in single arm studies - such as picking younger patients with lower risk

disease.

>

> E. Does this protocol manage the condition better than observation? . does it

improve survival or quality of life?

>

> Comment: With the emergence of many targeted therapies we have increased

potential to manage lymphoma by treating only as needed, or regularly with less

toxic doses when the protocol has less expected toxicity. Probably requires a

control group and random selection to objectively measure benefits and risks,

particularly if not all patients benefit, or benefits and adverse effects are

modest.

>

> F. Does adding a new agent (concurrently or sequentially) to an effective

protocol improve outcomes without substantially increasing risks?

>

> Example: the addition of Rituxan to CVP and CHOP. Related to other items above

- requires randomized studies and signficant follow up. A way to potentially

advance the standard of care by adding one agent and comparing with the standard

of care.

>

> G. Can we remove an agent from a curative protocol to decrease toxicity

without compromising it's efficacy?

>

> Comment: We see this question being asked in Hodgkins lymphoma, which has a

very high cure rate.

>

> H. Can use of this agent or protocol to delay the need for cytotoxic therapy

without burning bridges?

>

> Comment: We see this being studied for Rituxan as first therapy for indolent

lymphoma.

>

> I. Who is the new or approved agent/ protocol for? Who will benefit from it,

and who will only suffer unproductive side effects (should do something else)?

>

> Comment: Progress seem too slow on this front. Arguably, we do not need

another active drug nearly as much as how to predict who a drug is for. Who is

doing biomarker research? Does it require tissue? How can patients participate?

>

>

> =BACKGROUND:

>

> * How do you reliably measure benefits and risks?

>

> Response rate?

>

> Duration of response?

>

> Toxicities and risks secondary to toxicity, such as risk of infection?

>

> Impact on subsequent therapies?

>

> Survival benefit?

>

>

>

> An improvement in Survival is the most reliable endpoint or measure of

clinical benefit, because it accounts for known and unknown factors, but it is

not a practical measure for the indolent lymphomas because of the long survival

and opportunities we patients will have to try other treatments, which confound

assessment of any one.

>

> * A drug or protocol is said to provide clinical benefit for a specific

condition when the treatment improves quality of life or survival, relative to

the natural course of the disease.

>

>

>

> Because survival can be difficult to measure and compare in the indolent

lymphomas, progression free survival is a commonly used surrogate, thought to

reasonably predict survival benefit, but its significance depends on the

magnitude (months? Years?) and also possible offsetting toxicities.

>

>

>

> By law, the sponsor must provide clear and convincing evidence that a new drug

provides clinical benefit. The evidence from clinical data requires independent

data monitoring and most commonly a controlled and blinded study administered in

multiple centers.

>

> Another major goal of clinical trials is to help guide treatment decisions and

advance the standard of care, such as new uses of already approved treatments..

Treatment in regular clinical practice, case accounts, cannot inform or advance

clinical science in any meaningful way.

>

> All the best,

>

> ~ Karl

>

> Patients Against Lymphoma

> Patients Helping Patients

> Non-profit | Independent | Evidence-based

> www.lymphomation. org | Current News: http://bit.ly/f2A0T

>

> How to Help: www.lymphomation. org/how-to- help.htm

>

>

>

>

>

[Guest guest]

Thanks for asking, Adam,

My spouse has participated in three studies over 14 years. (idiotype vaccine,

hl22 antibody, and CpG with Rituxan).

She is a 14 year survivor of follicular lymphoma, a close cousin of CLL. I

don't feel that she was harmed, but we did not see any evidence of significant

clinical benefit. However, I am aware of patients who have benefited from study

participation.

Regarding bias, unfortunately, if you cast your net in the general pool of

published studies (PubMed), there are many stinking fish.

However, the standards for well-designed studies are well known by

investigators, regulators and journal editors. Standards include sufficient

sample size, a control group, that it's a multicenter study (not just one

investigator) and randomization.

There are a good number of reputable journals that review study data submissions

conscientiously ... that will be selective about publishing studies - will

reject studies that have biased methodology. NEJM. Journal of Clinical

Oncology, Nature etc. However, even the best journal review is not as

conscientious as FDA review, which is quite rigorous. However, FDA review is

only done for studies submitted to them by a sponsor for marketing approval.

I don't think it's rocket science to identify bias in clinical data reporting,

particularly if you've had opportunity to review studies submitted to FDA.

It's pretty common (according to statements made by the editors of the NEJM) to

see bias in the conclusion statements of abstracts .. and so there is a call to

leave out such information in clinical data reporting.

Unfortunately it's common for important detail (such as adverse events) to be

left out or insufficiently described in clinical study reports- particularly in

the abstracts and press releases.

One of the biggest problems in clinical science are the number of studies with

insufficient sample size and incomplete enrollment. Only one in 5 clinical

trials for cancer are ever published, mainly for this reason. See One in Five

Cancer Clinical Trials Is Published: A Terrible Symptom—What's the Diagnosis?

http://theoncologist.alphamedpress.org/cgi/content/full/13/9/923

There's no question in my mind that some studies can be as appropriate for

treatment as standard therapy ... and sometimes more appropriate. The challenge

is in identifying which study is the right fit for our clinical circumstances

and treatment goal. Every expert agrees that progress is not possible without

patient participation in clinical trials.

Karl

www.lymphomation.org

Re: Clinical Questions with comments

Karl -

1. Are you a CLL patient?

2. Have you volunteered for clinical trials?

3. If so, did the trial(s) benefit you in any way?

4. Were you harmed in any way?

Venkat's recent posting about clinical trials, in which she explores the

role of money and bias in clinical trials, is a useful adjunct to your post.

Adam

>

> Greetings,

>

>

> One of our major goals is to help patients understand the critical role of

clinical trials in making PROGRESS AGAINST LYMPHOMAS / CLL and to provide also

general guidance on when we may reasonably consider clinical trials.

>

>

>

> Please note that not all studies will have a control group and that a

placebo control (i.e., a sugar pill) is never used in oncology trials - the

control will be a standard of care.

>

> =SOME CLINICAL QUESTIONS THAT CAN ONLY BE ANSWERED BY TRIALS:

>

> A. Is this new drug effective when other agents are not?

>

> Comment: Answering this question doesn't require a randomized study if the

refractory status of the patients is well documented. Easiest path to marketing

approval - accelerated / conditional approval.

>

> B. Is protocol A better than protocol B for this type of lymphoma as first

therapy?

>

> Comment: This question is vital to advancing the standard of care †"

making evidence based treatment decisions. It can take a long time to accrue

patients and for data to mature. First treatment could be the best opportunity

to cure lymphomas or induce the most durable remissions which suggest a survival

benefit.

>

> C. Is protocol A better than protocol B for this type of lymphoma at first

relapse?

>

> Comment: Also vital to advancing the standard of care, improving survival

and helping to make evidence-based treatment decisions.

>

> D. Is this protocol curative, and if so does the curative potential outweigh

the risks?

>

> Comment: Takes a very long time for data to mature - up to 12 years for

indolent lymphomas. Historical controls may be sufficient, but studies need to

be large or replicated by independent groups. Patient selection bias is a

problem in single arm studies - such as picking younger patients with lower risk

disease.

>

> E. Does this protocol manage the condition better than observation? . does

it improve survival or quality of life?

>

> Comment: With the emergence of many targeted therapies we have increased

potential to manage lymphoma by treating only as needed, or regularly with less

toxic doses when the protocol has less expected toxicity. Probably requires a

control group and random selection to objectively measure benefits and risks,

particularly if not all patients benefit, or benefits and adverse effects are

modest.

>

> F. Does adding a new agent (concurrently or sequentially) to an effective

protocol improve outcomes without substantially increasing risks?

>

> Example: the addition of Rituxan to CVP and CHOP. Related to other items

above - requires randomized studies and signficant follow up. A way to

potentially advance the standard of care by adding one agent and comparing with

the standard of care.

>

> G. Can we remove an agent from a curative protocol to decrease toxicity

without compromising it's efficacy?

>

> Comment: We see this question being asked in Hodgkins lymphoma, which has a

very high cure rate.

>

> H. Can use of this agent or protocol to delay the need for cytotoxic therapy

without burning bridges?

>

> Comment: We see this being studied for Rituxan as first therapy for indolent

lymphoma.

>

> I. Who is the new or approved agent/ protocol for? Who will benefit from it,

and who will only suffer unproductive side effects (should do something else)?

>

> Comment: Progress seem too slow on this front. Arguably, we do not need

another active drug nearly as much as how to predict who a drug is for. Who is

doing biomarker research? Does it require tissue? How can patients participate?

>

>

> =BACKGROUND:

>

> * How do you reliably measure benefits and risks?

>

> Response rate?

>

> Duration of response?

>

> Toxicities and risks secondary to toxicity, such as risk of infection?

>

> Impact on subsequent therapies?

>

> Survival benefit?

>

>

>

> An improvement in Survival is the most reliable endpoint or measure of

clinical benefit, because it accounts for known and unknown factors, but it is

not a practical measure for the indolent lymphomas because of the long survival

and opportunities we patients will have to try other treatments, which confound

assessment of any one.

>

> * A drug or protocol is said to provide clinical benefit for a specific

condition when the treatment improves quality of life or survival, relative to

the natural course of the disease.

>

>

>

> Because survival can be difficult to measure and compare in the indolent

lymphomas, progression free survival is a commonly used surrogate, thought to

reasonably predict survival benefit, but its significance depends on the

magnitude (months? Years?) and also possible offsetting toxicities.

>

>

>

> By law, the sponsor must provide clear and convincing evidence that a new

drug provides clinical benefit. The evidence from clinical data requires

independent data monitoring and most commonly a controlled and blinded study

administered in multiple centers.

>

> Another major goal of clinical trials is to help guide treatment decisions

and advance the standard of care, such as new uses of already approved

treatments.. Treatment in regular clinical practice, case accounts, cannot

inform or advance clinical science in any meaningful way.

>

> All the best,

>

> ~ Karl

>

> Patients Against Lymphoma

> Patients Helping Patients

> Non-profit | Independent | Evidence-based

> www.lymphomation. org | Current News: http://bit.ly/f2A0T

>

> How to Help: www.lymphomation. org/how-to- help.htm

>

>

>

>

>