# Presentation: 171290

## Ethics of Phase I Oncology Trials

- Manish Agrawal M.D., M.A.
- Department of Clinical Bioethics
- Medical Oncology Clinical Research Unit
- National Institutes of Health

## Phase I Research

- Phase I research is research aimed at identifying the safety, toxicities and the appropriate dosing of a new drug or intervention for future efficacy studies (Phase II).

## 8 Requirements for Ethical Research

- 1) Collaborative partnership
- 2) Social value
- 3) Scientific validity
- 4) Fair subject selection
- 5) **Favorable risk-benefit ratio**
- 6) Independent review
- 7) **Informed consent**
- 8) Respect for human subjects

## “ ...Phase I cancer drug research, for example, may not be performed on terminally ill subjects under these guidelines because there is no reasonable probability that it will benefit the subjects.”
						-George Annas

- 						-George Annas

**What the Critics Say**

## Another Critic

- “Informed consent documents make phase one studies sound like the cure for your cancer”
- 						LeRoy Walters (2000)

## Ethical Criticisms of Phase I Oncology Research

- Unfavorable Risk Benefit Ratio
- Informed Consent is flawed

## Risk/Benefit Ratio

- Critics argue that the risks outweigh the benefits
- Some even argue that there are risks with no benefits

## Decoster et al. (1990)

	Reviewing 211 trials involving 87 drugs and 6,639 patients between 1972-1987.

Complete Responses			0.3%

Partial Responses			4.2%

Toxic deaths				0.5%

- 	Reviewing 211 trials involving 87 drugs and 6,639 patients between 1972-1987.
- Complete Responses			0.3%
- Partial Responses			4.2%
- Toxic deaths				0.5%

**What are the Benefits? **

## Estey et al. (1986)

	Reviewing 187 trials involving 54 drugs and 6,447 patients between 1974-1982.

Complete Responses		0.7%

Partial Responses		3.5%

- 	Reviewing 187 trials involving 54 drugs and 6,447 patients between 1974-1982.
- Complete Responses		0.7%
- Partial Responses		3.5%

**What are the Benefits?**

## Toxic Death 0.5%

Side effects- Neutropenia, hair loss, neuropathy; severity and prevalence is not quantified

- Side effects- Neutropenia, hair loss, neuropathy; severity and prevalence is not quantified

**What are the Risks?**

## Resource and time commitment from patients and families; due to frequent blood draws, radiological evaluations, physician visits, biopsies etc.

**What are the Risks?**

## Do the data as discussed tell the whole story?

## Overall response rates may hide important response data:

30% of the drugs from the meta-analyses had response rates over 5%
Only 39% of the trials had no objective responses
The meta-analyses only looked at drugs from 1972-1987, the drugs used now are better.

- 30% of the drugs from the meta-analyses had response rates over 5%
- Only 39% of the trials had no objective responses
- The meta-analyses only looked at drugs from 1972-1987, the drugs used now are better.

**A Second Look at the Meta-analyses**

## Some remarkable therapeutic benefits in Phase I oncology trials

Platinum had >50% response rate in testicular cancer

Gleevac had >90% response rate in CML

- Platinum had >50% response rate in testicular cancer
- Gleevac had >90% response rate in CML

**Some Notable Responses in Phase I Studies**

## More Recent Data on Risks/Benefits

- 	CTEP Database
- 460 trials between 1991 and 2002
- 10,402 patients for response
- 11,935 patients for toxicity

## Risk-Benefit Ratio

- Yesterday’s Phase I is not today’s Phase I.
- Nature of Phase I oncology studies have changed.  They are no longer only trials of “first in man” chemotherapeutic agents.

## Risk-Benefit Ratio

- 	Review of CTEP Phase I data from 1991-2002
- 21% single investigational chemotherapeutic agent.
- 42% single investigational agent of any kind.
- 55% multiple investigational agents.
- 45% include at least one proven agent.

## Risk-Benefit Ratio

|  | RR | CR | SD |
| --- | --- | --- | --- |
| Overall (460 agents) | 10.6% | 3.1% | 34.1% |
| 1 Invest Chemo Agent (20%) | 4.4% | 1.5% | 40.8% |
| Multiple Invest Chemo Agent (2.6%) | 11.7% | 1.5% | 27.5% |
| Approved and Invest    Chemo Agents (19%) | 16.4% | 5.6% | 31.3% |
| 1 Invest Signal Transd. Agent (11%) | 3.2% | 0.7% | 39.3% |

## Risk-Benefit Ratio

|  | Death | Grade IV Toxicity |
| --- | --- | --- |
| Total (11,935) | 0.49% | 14.3% |
| 1 Invest Chemo Agent (2,621) | 0.57% | 15.0% |
| Approved and Invest Chemo  Agent (2,594) | 0.77% | 14.5% |
| 1 Invest. Sign Transd  (1,565) | 0.19% | 13.0% |

## Risk-Benefit Ratio

| CR | PR | SD | Deaths |
| --- | --- | --- | --- |
| 3.8% | 15.2% | 23.0% | 1.1% |

**211 Phase I studies published in 2002**
**6,008 participants evaluable for toxicity**
**5,362 participants evaluable for response**

## 	

	“...Patients do not seem to be harmed by their experience of participating in a phase I trial and may experience benefits, albeit not in terms of tumor control” 			
							Moore (2001) 

- 	“...Patients do not seem to be harmed by their experience of participating in a phase I trial and may experience benefits, albeit not in terms of tumor control”
- 							Moore (2001)

**Benefits beyond Tumor Responses**

## 

If we are going to consider non-medical risks, we should also consider non-medical benefits.

- If we are going to consider non-medical risks, we should also consider non-medical benefits.

**Benefits beyond Tumor Responses**

## Some data suggest that enrolling in Phase I research is beneficial to the quality-of-life of patients.
Patients in Phase I had stable Quality Of Life and performance status over 1 course of therapy whereas similar patients receiving supportive care had declines in QOL.

					Melink et al. (1992), Berdel et al. (1988)

- Patients in Phase I had stable Quality Of Life and performance status over 1 course of therapy whereas similar patients receiving supportive care had declines in QOL.
- 					Melink et al. (1992), Berdel et al. (1988)

**Other Benefits Beyond Tumor Response**

## 
65% of research participants said they believed they would receive psychological benefit from being in the phase I study.
Structure and routine of trials
Exercise some control
Help others in the future

						Daugherty et al. (2000) 

- 65% of research participants said they believed they would receive psychological benefit from being in the phase I study.
- Structure and routine of trials
- Exercise some control
- Help others in the future
- 						Daugherty et al. (2000)

**Psychological Comfort**

## Risks may not be as bad as implied.  

0.7% risk of death for a terminally ill patient may not be very high.

It would be good to have more data on the risks of other side effects and morbidity rates.

- 0.7% risk of death for a terminally ill patient may not be very high.
- It would be good to have more data on the risks of other side effects and morbidity rates.

**Summary of Risks **

## Benefits may be greater than implied.

Many Phase I drugs trials have had >15% response rates and at least 2 notable cases have provided substantial therapeutic responses even cures.

QOL may be better on a Phase I trial than supportive care.

- Many Phase I drugs trials have had >15% response rates and at least 2 notable cases have provided substantial therapeutic responses even cures.
- QOL may be better on a Phase I trial than supportive care.

**Summary of Benefits**

## While the scientific objectives of phase I oncology studies do not include patient benefit, there do appear to be benefits.
Are the benefits enough to make risk/benefit ratio favorable?

- Are the benefits enough to make risk/benefit ratio favorable?

**What do the Data Show?**

## Is the risk/benefit ratio favorable or unfavorable?

## Compare Results of Phase I Studies to FDA Approved Chemotherapy 

- High dose IL-2 for metastatic renal cell
- 		Complete Response	5%
- 		Partial Response		9%
- 		Median duration of response is 20 months
- Gemcitabine approved for improvement in QOL for pancreatic cancer with response rate of only 5%

## Compare Results of Phase I Studies to FDA Approved Chemotherapy

- Topotecan is approved with 10% response rate for ovarian cancer.
- CPT-11 is approved for metastatic colon cancer on the basis of less than 2 month prolongation of survival
- 1% gain in absolute mortality for 4 cycles of adjuvant chemotherapy for Stage I breast cancer.

## Risk-Benefit Ratio Not Worse than Other Approved Therapy by FDA 

- The risk-benefit ratio for phase I oncology studies is clearly not worse than risk/benefit ratios used by the FDA as a basis for approval of many chemotherapeutic agents.

## Who decides what is a favorable risk benefit ratio?

## Who decides?

- Who currently decides a favorable risk-benefit ratio in research?
- Investigators
- Bioethicists
- Lawyers
- Statisticians
- Physicians
- Policymakers

## Who Should Decide?

- Should the people who are facing life-ending illness have some input on whether a risk/benefit ratio is favorable for research studies?

## Patients Have Different Perceptions than Healthy People  

- Substantial data demonstrates that patients facing serious illnesses make very different assessments of their own condition and the risks they are willing to confront compared to healthy individuals.
- Even families, consistently overestimate symptoms and underestimate patient satisfaction and quality of life
- 						Epstein (1989), Zweibel (1989)

## Patients need very small benefits to find cancer chemotherapy worthwhile.
Cancer patients only needed only 1% chance of benefit to want an intensive chemotherapy regimen described with many side effects.
Nurses needed 50% chance, and doctors needed a 10% chance, general public needed 50% chance of benefit.
							Slevin et al. 1990

- Cancer patients only needed only 1% chance of benefit to want an intensive chemotherapy regimen described with many side effects.
- Nurses needed 50% chance, and doctors needed a 10% chance, general public needed 50% chance of benefit.
- 							Slevin _et al._ 1990

**Patients Willing to Undergo More Risk than Healthy People**

## A patient’s perspective

- 	We who are struggling to escape cancer do not, obviously, want to die of it.  We do prefer death in the struggle to life under cancer’s untender rule.  The enemy is not pain or even death, which will come for us in any eventuality.  The enemy is cancer, and we want it defeated and destroyed... This is how I wanted to die—not a suicide and not passively, but eagerly in the struggle.
- 				George Zimmer
- 				Phase I patient University of Chicago

## Patient’s Perspective Should be Taken into Account

- Views of terminally ill cancer patients should inform IRB determinations of favorable risk-benefit ratios for phase I oncology studies.
- Including such patients might emphasize alternative study designs using higher doses that increase toxicities but also may increase the chance of benefits

## Ethical Criticisms of Phase I Oncology Research

- Unfavorable Risk Benefit Ratio
- Informed Consent

## Disclosure
Are Phase I informed consent documents distortive?
Understanding
Do terminally ill patients understand information about Phase I research?
Voluntariness
Are terminally ill patients able to choose freely?

- Are Phase I informed consent documents distortive?
- Understanding
- Do terminally ill patients understand information about Phase I research?
- Voluntariness
- Are terminally ill patients able to choose freely?

**Invalid Informed Consent**

## Invalid Informed Consent

- Problems with disclosure of information
- Physicians do not provide appropriate  or accurate information.
- Physicians stress and exaggerate the benefits while minimizing the risks of research participation.

## Invalid Informed Consent

- Problems with patient understanding.
- Because they are terminally ill, patients cannot understand the true objectives, benefits and risks of Phase I research.  Their understanding  is clouded by their physical state and their hope for a cure.
- What clear thinking patient would opt to take toxic drugs rather than receive palliative care and comfort measures at the end of life?

## Invalid Informed Consent

- Because terminally ill patients are not given proper information by their physicians, because they cannot understand the information they are given, and because they are vulnerable, they cannot provide valid informed consent.

## Informed Consent

- 	Can terminally ill patients provide informed consent?
- Do Phase I researchers misinform patients?
- Do Phase I informed consent documents misinform?
- Do terminally ill patients misunderstand information about Phase I research?
- Are terminally ill patients under a therapeutic misconception?
- Are terminally ill patients vulnerable?

## Do Phase I Researchers Misinform Patients?

## Do Physicians Misinform?

- Tomamichel _et al._ (1995)
- Recorded informed consent interactions for 32 patients.
- Quantitative analysis indicated that 3 major information points were communicated in almost 80% of cases.
- Use of indirect patient responses was not as good.

## Do Physicians Misinform?

- 	Daugherty _et al._ (1995)
- 	18 Phase I oncologists at U of Chicago
- 	1-2 months added survival			10%
- 	Complete and partial response		15%
- 	Complete response				1%
- 	Life-threatening toxicity			10%
- 	Death					5%

## Do Physicians Misinform?

| Discussed with Patients | Physicians | Patients |
| --- | --- | --- |
| Possible side effects | 92% | 78% |
| Possible risks | 92% | 73% |
| Possible benefits | 90% | 79% |
| Change in length of life | 60% | 29% |

- Meropol _et al._ (2003)
- 48 physicians and 328 patients considering Phase I

## Do Physicians Misinform?

- Limited data suggests physicians do not misinform patients and if they do misinform they tend to over-estimate risks more than benefits.

## Do Phase I  Informed Consent Forms Misinform?

## Informed Consent Forms

- Are Phase I informed consent forms distorted?
- 	Do they over promise benefits?
- 	Do they minimize risks?

## Do Forms Misinform?

- 	Data from a review of 272 Phase I informed consent documents from 1999.
- Only 29% of all Phase I oncology trials involve a previously untested drug in classic dose escalation design.
- 40% of Phase I trails had a therapeutic element.  For instance, adding a new drug to a known effective drug.
- 						Horng et al. (NEJM, 2002)

## Do Forms Misinform?

- 92% mention safety, dose determination, or toxicity as the purpose of the trial.
- 99% mention that the study is research or an experiment with most of these being prominent or highly prominent in the informed consent form.

## Do Forms Misinform?

- 6% explicitly mention that the research is not therapeutic.
- 96% refer to the chemotherapy agent as treatment or therapy.

## Do Forms Misinform?

- Median length of risk and benefit sections
- 		Risk			35 lines
- 		Benefit		4 lines
- 67% mention death as a possible risk
- 33% mention death more than once
- 83% mention possibility of serious harms

## Do Forms Misinform?

- One of 272 forms mention benefits will definitely accrue to subjects.
- Mention as possible benefits
- 		Cure					5%
- 		Life prolongation			20%
- 		Tumor shrinkage			36%
- 		Generalizable knowledge		68%

## Do Forms Misinform?

- 96% have separate alternatives section
- Mention as  alternatives
- 		Palliative care				56%
- 		Standard therapy				88%
- 		No treatment				65%
- 		Other experimental therapy		52%
- 		Hospice					<1%

## Do Forms Misinform?

- 	While the documents are not perfect and can be improved, it is hard to say that informed consent documents:
- Over promise benefits and minimize risks
- Disguise the nature of the trial or that it is research
- Promise cure

## Do Patients with Advanced Cancer Misunderstand Information about Phase I Research?

## Do Patients Misunderstand?

- Decoster _et al._ (1990)
- 91% of patients on Phase I trials had prior therapy:
- 50% chemotherapy alone
- 25% chemotherapy and radiation therapy
- 11% radiation therapy alone

## Do Patients Misunderstand?

- Daugherty _et al._ (2000)
- 	Recall signing consent form				100%
- 	Recall explanation of study as research	  	98%
- 	Recall explanation of risks and side effects  	  97%
- 	Recall at least 1 specific side effect			100%
- 	Felt well informed				 	 96%
- 	Quality of the information transfer was associated with higher education.

## Do Patients Misunderstand?

- 	Joffe _et al._ (2001)
- 	Mailed survey of 207 Phase I, II, and III cancer patients.
- 	50 in Phase I studies, but not distinguished in data analysis.

## Do Patients Misunderstand?

- 	Joffe _et al._ (2001)
- 84% read the consent form carefully
- 87% had enough time to learn about the trial
- 93% sufficient time to ask questions
- 48% consent discussion last over 1 hour
- 44% consulted an outside physician

## Do Patients Misunderstand?

- Almost all patients participating in Phase I studies feel well informed and are satisfied by the informed consent process:
- _	__	__Study__	__	__  # of Patients__	__     % Satisfied_
- 	Daugherty	   		144			     96%
- 	Tomamichel 	     	31			     96%
- 	Joffe		  	 207			     90%

## Do Terminally Ill Patients have a Therapeutic Misconception about Phase I Trials?

## Therapeutic Misconception?

- 	_Study       # Subjects __	__       Results  _
- 	Yoder 	         	37	    	70% to get best care
- 					    	85% shrink tumor
-  	Tomamichel  	31	    	59% medical benefit
- 	Cheng	         	30        		60% medical benefit

## Therapeutic Misconception?

- Daugherty _et al._ (2000)
- 	Patients views of purpose of Phase I
- 	Anticancer Response		61%
-   Toxicity Determination	27%
-   Combination			  8%

## Therapeutic Misconception?

- 	Meropol _et al._ (2003)
- 	Maximum Benefit of Experimental Therapy
- 	37% of studies only investigational agents
- Totally cure				39%
- Reduce cancer			26%
- Control cancer			30%
- Improve symptoms			3%
- Nothing				2%

## Therapeutic Misconception?

- 	Joffe _et al._ (2001)
- 75% reported that the main reason for trials was to improve treatment of future patients
- 71% there may not be direct medical benefit to me
- 48% report treatments and procedures in the trial are standard for their cancer

## Elizabeth

- 	“I know you want me to say that this trial is about safety.  But the doctors wouldn’t start the trial without hoping they could prove the drug would be effective in stopping cancer in future trials.”

## Disclosure
Are Phase I informed consent documents distortive?
Understanding
Do terminally ill patients understand information about Phase I research?
Voluntariness
Are terminally ill patients able to choose freely?

- Are Phase I informed consent documents distortive?
- Understanding
- Do terminally ill patients understand information about Phase I research?
- Voluntariness
- Are terminally ill patients able to choose freely?

**Invalid Informed Consent**

## The Ethical Concern Raised about Voluntariness

- Some critics argue that terminally ill patients not only have clouded understanding and are not acting voluntarily but under compulsion by their impending death.

## 
No data on the voluntariness of the informed consent process in phase I cancer studies

- No data on the voluntariness of the informed consent process in phase I cancer studies

**Voluntariness**

## We Don’t Ignore Other Decisions People Make at the End of Life

- Just facing terminal illness does not invalidate people’s decisions
- We accept estate wills and DNR requests made by terminally ill patients as genuineWe do not reject the consent of life-saving organ transplants as prima facie invalid because they are made by terminally ill patients who cannot think clearly

## Cannot Label Everyone with Advanced Cancer as Incompetent

- There will be some people with advanced cancer who are able to and do make rational , reasonable, informed decisions and some who can’t just like those without advanced cancer
- But cannot conclude that all patients with advanced cancer are unable to give informed consent

## Summary

- Risk-Benefit ratio is not unfavorable
- There are more benefits than ascribed by critics
- The Risk-Benefit ratio is not clearly worse than some FDA approved therapy
- Patients perspective should be taken into account when deciding about risk-benefit ratios
- Data does not suggest that consent is uninformed