Deadly Diseases and People of Color:Are Clinical Trials an 
Option?

Symposium

October 25, 1996

Howard UniversityWashington, D.C.

Presented by:

U.S. Food and Drug AdministrationHoward University College 
of MedicineMid-Atlantic AIDS Education and Training CenterD.C. Local 
Performance Site at Howard Universityin cooperation withMaryland AIDS 
Professional Education CenterHoward University School of Continuing 
EducationContract No. 277-95-2024

**Symposium Index**

Overview

Welcome and Opening 
RemarksCelia Maxwell, M.D.,F.A.C.P.Eric Goosby, M.D.Vinod Mody, 
M.D.Sharon Smith Holston

Panel: New 
Therapies for Diseases Affecting Communities of Color, Moderator: Celia 
Maxwell, M.D.,F.A.C.P.Panelists:Hypertension: Otelio Randall, M.D., 
F.A.C.C. AIDS: David Feigal, M.D., 
M.P.H. Diabetes: Wayman Cheatham, 
M.D. Prostate Cancer: Judd Moul, M.D., 
F.A.C.S.

Panel: Diverse 
Perspectives of Clinical Trials Moderator: Linda Ann Sherman, 
M.D.Panelists:FDA: Jonca Bull, M.D., 
F.A.A.O. Human Subjects Protection: Warren Ashe, Ph.D. 
Patient: Gregory 
Hutchings Community: Otis Brawley, 
M.D. Academia: Wayne Greaves, M.D., 
F.A.C.P. Industry: James Powell, 
M.D.

Panel: Expanded 
Access Mechanisms and Managing Costs of Clincal Trials and Investigational 
Therapies Moderator: Theresa Toigo, R.Ph., M.B.A.Panelists:Expanded 
Access:   Heidi Jolson, M.D., 
M.P.H. AIDS Drug Assistance: Steven Young, 
M.P.H. Managed Care: Mary McCabe, R.N. 
Medicad/Medicare: Gerald Zelinger, 
M.D.

Appendix 1 
- Symposium Faculty

End

**Overview**

On October 25, 1996, the symposium entitled "Deadly Diseases and People of 
Color: Are Clinical Trials An Option?" was held at Howard University in 
Washington, D.C. The symposium comprised three panel sessions that addressed the 
benefits of and barriers to clinical trial participation by physicians and 
patients of color. Symposium participants learned about new treatments for 
hypertension, AIDS, diabetes, and prostate cancer--serious diseases that 
disproportionately affect communities of color. They also learned about the role 
of clinical trials in developing therapies for these diseases and improving 
access of minority populations to promising new therapies. In addition, 
participants reviewed the process used by the Food and Drug Administration (FDA) 
to evaluate new therapies for safety and efficacy and the regulatory mechanisms 
used to enhance patient access to promising new therapies. Participants also had 
an opportunity to examine the impact of managed care on the conduct of clinical 
trials. Finally, participants learned the extent to which Medicaid and Medicare 
cover investigational therapies.

Symposium faculty comprised distinguished medical research scientists from 
the public and private sectors, community leaders, health care providers, and 
representatives from FDA. (A list of symposium faculty can be found in Appendix 1.)

The following summary presents key points raised in the presentations and in 
the discussion periods that followed each panel session.

Welcome and Opening Remarks

Celia Maxwell, M.D., F.A.C.P.Eric Goosby, M.DVinod Mody, 
M.D.Sharon Smith Holston

Dr. Celia Maxwell, Special Assistant for the Commissioner, Food and Drug 
Administration (FDA) and Assistant Professor of Medicine, Howard University 
Hospital, welcomed everyone and complimented symposium organizers for their hard 
work. Reviewing the day's agenda, she explained that the symposium was intended 
to explore the issues that prevent people of color from participating in 
clinical trials. Next, Dr. Eric Goosby, Director of the Office of HIV/AIDS 
Policy, Department of Health and Human Services (DHHS), conveyed greetings from 
the Secretary, DHHS, and revealed that the Secretary had included the symposium 
in her weekly report to the President. Dr. Goosby emphasized that DHHS is 
committed to supporting similar symposia with community leaders and members of 
the medical profession with the aim of increasing the availability of clinical 
trials in communities of color and ultimately ensuring that underserved patients 
are entered into a continuum of care.

During his remarks, Dr. Vinod Mody (Howard University College of Medicine) 
stated the importance of ensuring that underserved populations who participate 
in clinical trials are also able to benefit from the trial results. He commented 
on the timeliness of the symposium, noting "as we enter the new century we must 
[ensure] that people of color have access to health care and new technologies . 
. ."

Sharon Smith Holston (FDA) presented the agency's perspective on the 
importance of clinical trials. She began by stating that FDA's public health 
mission is to ensure that drugs and other health care products used in the 
United States are safe and effective for all Americans. She added that 
the main tool for accomplishing this is a well-conducted clinical trial, which 
provides the evidence of safety and effectiveness needed for approval by FDA. 
Clinical trials also are indispensable for pursuing the science of 
medicine--without them, scientific progress would be "paralyzed."

Ms. Smith Holston briefly described some of the steps taken by FDA to (1) 
make clinical trials a more flexible and effective instrument for the 
development of new therapies for serious and life-threatening illnesses, and (2) 
increase the access of patients to promising experimental drugs. In the 
mid-1970s, for example, FDA allowed beta blockers to be used for seriously ill 
patients who could not use other types of drugs. In the 1980s, (partially) in 
response to the AIDS epidemic, FDA introduced the Treatment Investigational New 
Drug (IND) and "parallel track " mechanisms to enable HIV patients to receive 
promising new therapies that were still in development and not yet approved by 
FDA. Another mechanism, the Orphan Drug Act, encourages pharmaceutical companies 
to develop treatments for rare diseases. Recently, FDA has accelerated the 
availability of important new cancer therapies by approving them on the basis of 
surrogate endpoints.

Other steps taken by FDA include establishing the Office of AIDS and Special 
Health Issues and the Office of Women's Health. These offices are intended to 
keep the agency alert to the needs of groups with special health care problems. 
FDA has also responded to the needs of special populations by enhancing its 
regulatory requirements. For example, to increase the inclusion of women in 
clinical trials, FDA now requires gender analysis as part of the evidence of a 
drug's safety and effectiveness.

Ms. Smith Holston noted, however, that much remains to be accomplished in 
terms of bringing people of color into the drug development process. Today, 
about one-fourth of the U.S. population are people of color; by 2050, nearly 
half (48 percent) will be. Yet, only 5 percent of clinical trial participants 
are members of minority groups. She added that this situation is 
"unacceptable"and that FDA intends to do its share to bring about a much-needed 
improvement.

The issue of increasing minority participation in clinical trials is 
important on two levels: first, its significance for public health; second, its 
contribution to the Nation's commitment to the principles of equality and 
fairness. Indeed, the participation of people of color in clinical trials must 
increase rapidly "if the public health protection system, the pharmaceutical 
industry, and medical science are to truly serve the needs of the entire 
nation."

Panel: New Therapies for 
Diseases Affecting Communities of Color

Moderator: Celia Maxwell, M.D., F.A.C.P.Panelists: 
Hypertension--Otelio Randall, M.D., 
F.A.C.C.AIDS--David Feigal, M.D., 
M.P.H.Diabetes--Wayman Cheatham, 
M.D.Prostate Cancer--Judd Moul, M.D., 
F.A.C.S.

**Hypertension**

**Dr. Otelio Randall**(Howard University College of Medicine) 
reviewed the different therapeutic approaches for treating hypertensive 
patients. Dr. Randall reported that hypertension (i.e., high blood pressure) is 
extremely common, affecting about 43 million Americans. Hypertension is a major 
risk for many conditions such as congestive heart failure, coronary artery 
disease, and kidney disease.

African Americans and Hypertension

African Americans are at particularly high risk for hypertension. In fact, 
they experience higher blood pressure levels at a younger age than any other 
ethnic group. This, in turn, results in higher hypertension-related morbidity 
and mortality rates among African Americans. Dr. Randall noted, for example, 
that end-stage renal disease is 4 to 18 times higher among African Americans, 
with prevalence rates peaking among 25- to 44-year-olds. He also observed that 
even though cardiovascular disease rates generally are declining (chiefly 
because of diuretics and other treatments), the rates are not declining as fast 
among African Americans as in other U.S. populations.

**Clinical Trials for Hypertension Therapies**

Dr. Randall then discussed clinical trials that had been conducted to develop 
hypertension therapies. First, he offered the following definition of a clinical 
trial: "The acquisition of data on a well-defined population, usually randomized 
to single blind, double blind, or triple blind fashion, with certain designs to 
determine any significant differences in the different treatment arms."

Dr. Randall emphasized the importance of having adequate representation of 
women and minorities in clinical trials, so that any treatment differences could 
be identified. He described the first clinical trial for hypertension, which 
demonstrated that hypertension-related mortality and morbidity could indeed be 
reduced among African-American patients. The trial included enough African 
Americans in the cohort so that trial results could be extrapolated with 
confidence to this population. During his presentation, Dr. Randall mentioned 
the African-American Study of Kidney Disease (AASK) clinical trial currently 
being conducted to determine if kidney disease can be prevented by reducing 
blood pressure. The trial is being conducted at 20 centers, including Howard 
University, and will enroll over 1,030 patients.

**Current Treatments for Hypertension**

Dr. Randall discussed the classes of drugs currently being used to treat 
hypertension, such as calcium channel blockers, angiotensin converting enzyme 
inhibtors (ACE Inhibitors or ACE-Is), AT-1 receptor blockers, angiotensin II 
receptor blockers, and post-alpha synoptic blockers. He reviewed data from 
clinical trials which demonstrate that specific classes of drugs are more 
effective for certain population groups, more protective of target organs, and 
more effective in the presence of concomitant conditions. These findings 
demonstrate that physicians should consider multiple factors when determining 
the treatment of choice for an individual patient; specifically:

- The patient's demographic profile (e..g, race/ethnicity, gender, age)
- The type of hypertension (e.g., diastolic, systolic, combined extension) 
  and stage (e.g., I, II, III, or IV)

- The type of concomitant condition (e.g., diabetes mellitus, coronary 
  artery disease), and

- The pharmacologic characteristics of the available therapeutics.

The physician should then "mix and match" these variables to determine the 
treatment strategy. Dr. Randall led symposium participants through the 
decisionmaking process and treatment steps for treating hypertensive patients 
with renal failure, congestive heart failure, and coronary heart disease. For 
example, diuretics are more effective than ACE-Is in treating patients with 
kidney disease. ACE-Is, however, are the first choice for treating hypertensive 
patients who have diabetes mellitus. ACE-Is are also the first choice for 
treating patients with congestive heart failure. But for hypertensive patients 
with coronary artery disease, beta blockers are the first treatment choice.

**AIDS**

**Dr. David Feigal** (FDA) discussed the evolution of current 
therapies for HIV infection, and he reviewed the data gleaned from clinical 
trials regarding the benefits and limitations of these therapies. Dr. Feigal 
also reviewed the role that FDA's accelerated approval mechanisms play in making 
promising new AIDS drugs available to patients earlier in the drug development 
process. To illustrate his point, throughout his presentation, Dr. Feigal showed 
a series of graphs that indicated which drugs were available in any given year 
for people with HIV. These graphs revealed that FDA's accelerated approval 
mechanisms enabled patients to receive promising drugs 3-5 years earlier than 
would be possible using conventional drug approval mechanisms.

Dr. Feigal began his presentation by noting several milestones in the 
development of AIDS therapies: identification of HIV virus, development of blood 
tests that allowed diagnosis and helped to ensure a safer blood supply, 
development of sensitive measurements of viral load, development of tools to 
monitor immune function, and understanding the methods of virus transmission 
(i.e., unsafe sex, contaminated needles, and mother/child transmission).

He explained that at any given time, about 250 new HIV agents are under 
study; the "success" rate is about one in ten. The targets of these drug 
development studies are: virus/cell binding mechanisms (e.g., CD4), virus genome 
decoding (i.e., reverse transcriptase [RT]), virus genome integration (i.e., 
integrase), virus protein regulation, and viral protein assembly (i.e., 
protease).

First Era of HIV Drug Discovery

The "first era" of HIV therapeutics to target the virus consisted of the 
nucleoside RT inhibitors (i.e., AZT, ddI, ddC, d4T). Clinical trials were key to 
discerning the benefits and drawbacks of this class of drugs. Trial results 
showed, for example, that AZT prevented mother/child transmission and that RT 
inhibitors had greater effectiveness when used in combination than when used 
alone. However, clinical trials also revealed the drugs' limitations. Antiviral 
effects were modest; it was unusual for a patient to completely suppress HIV 
replication. Furthermore, effectiveness was time-limited; resistance developed 
on average in about a year if a drug was used alone. In addition, many of 
nucleoside RT inhibitors had dose-limiting toxicity. For example, AZT patients 
often developed neutropenia; ddI patients developed pancreatitis.

Second Era of HIV Drug Discovery

Dr. Feigal discussed recent developments that have led to a "second era" of 
HIV drug discovery. These include more sensitive methods to assess a drug's 
effect on viral load, thus allowing drug resistance to be detected more easily. 
In addition, four new drugs have been developed: a non-nucleoside reverse 
transcriptase inhibitor (i.e., nevirapine), three protease inhibitors 
(saquinavir, ritonavir, indinavir), which, when used in combination with other 
therapies, can have a powerful effect on reducing viral load. The combined use 
of different classes of drugs enables treatment to focus on more than one viral 
target simultaneously.

Other therapeutics are also under investigation. These include an agent that 
targets integrase, and interferon, an immunomodulator. The latter is approved 
for treatment of Kaposi's Sarcoma and is being studied for its effects in 
combination with nucleoside analogs.

Lessons Learned

Dr. Feigal summarized the lessons learned to date from clinical trials 
regarding HIV therapies:

- Physicians should carefully consider the choice of initial therapy, 
  because HIV drugs are most effective in therapy-naive patients.

- Monotherapy should not be the initial treatment approach; instead, 
  physicians should start with the best drug combination available. The more 
  severe the patient's disease, the more drugs should be used in combination.

- Patient compliance and adequate dosing are important. For example, 
  patients who miss doses or who are on too low a dose develop resistance.

- Patients with low CD4 counts are producing a large number of CD4 cells; 
  when viral replication is controlled, CD4 counts can rise dramatically.

- Viral load is a strong predictor of disease activity. (During the last 
  year a kit for measuring viral load has been made commercially available to 
  clinical labs.)

- Suppression of viral replication prolongs the usefulness of initially less 
  effective drugs.

Participation in Clinical Trials

During his presentation, Dr. Feigal discussed the importance of minority 
group participation in clinical trials. Participation is integral to the 
development of new therapies, and it also increases a patient's treatment 
options. In addition, having sufficient numbers of minority study subjects helps 
provide an accurate assessment of a drug's treatment effects. For example, a 
Veterans Administration (VA) study of early versus delayed AZT treatment showed 
that early treatment did not appear to have much benefit for Hispanics and 
African Americans. In this case, FDA examined pooled data from other studies and 
determined that the VA finding was a "false signal" because it was based on a 
relatively small sample of minority patients. Dr. Feigal also observed that 
another difficulty in detecting treatment effects is when the different effects 
are due to factors such as unequal access to health care.

Diabetes

The next panelist, **Dr. Wayman Cheatham** 
(Howard University College of Medicine) described new approaches for treating 
diabetes. He began by noting that diabetes is the third leading cause of death 
in the United States, affecting 16 million people. Of these, only 8 million have 
been diagnosed and less than one-half of these individuals are receiving 
appropriate treatment. In 1995, the cost of caring for and treating diabetic 
patients reached $100,000 billion.

Risk Factors for Diabetes

Risk factors for diabetes include having a family history of diabetes, being 
overweight, advancing age, and being from a minority ethnic group. Dr. Cheatham 
explained that people of color are disproportionately affected by diabetes. One 
in 22 white Americans have the disease, compared with 1 in 14 African Americans, 
1 in 7 Hispanics, and 1 in 3 Native Americans. He recounted that among the Pima 
Indian tribe of Arizona, 1 in 2 people over age 35 has Type II diabetes. 
Diabetes-related mortality rates are also higher among people of color than 
among whites.

Etiology of Diabetes

Diabetes is a condition characterized by elevated blood sugar. Affected 
individuals cannot use all of the glucose provided by the food they eat or 
produced by the liver. Dr. Cheatham emphasized, however, that diabetes is not 
**caused** by high blood sugar. High blood sugar is only a sign of 
the metabolic abnormalities that are collectively called diabetes. These 
metabolic abnormalities start long before blood sugar levels rise; therefore, 
early diagnosis and treatment can reduce or prevent diabetes-related morbidity 
and mortality.

Dr. Cheatham then offered the following classification system for diabetes 
mellitus:

- Type I (This usually occurs in children, but there are also many 60- to 
  80-year-olds with Type I. Individuals with Type I diabetes have an insulin 
  deficiency.)

- Type II (This usually occurs in an older age group and is characterized by 
  a gradual onset of symptoms.)

- Pregnancy complications

- Impaired glucose tolerance (Prevalence increases as people age and 
  increase in weight.)

Dr. Cheatham described the process by which insulin binds to the cell 
receptor and transports glucose, sodium, potassium, and calcium to the cell, and 
noted that a number of different disorders can lead to glucose elevation. He 
noted that there are three disorders that represent Type I diabetes and five 
disorders that represent Type II diabetes. Interestingly, among the various 
ethnic groups, different genetic markers have been found that appear to cause 
the same type of disease.

Complications from diabetes include cardiovascular disease; eye, kidney, and 
nerve damage, and impotence. Dr. Cheatham noted that hypertension occurs in 
about 60 to 80 percent of people with Type II diabetes. Furthermore, there is 
thought to be a link between the resistance to insulin that characterizes people 
with Type II diabetes and changes in the way the cell responds to sodium and 
calcium. He commented that two studies are underway to evaluate patients with 
concomitant diabetes and hypertension.

Diabetes Diagnosis and Treatment

Currently, there is no way to diagnose diabetes other than measuring glucose 
levels. Research is underway, however, to discover markers that can identify 
people who are at risk for developing diabetes. In Type II patients, for 
example, hypertension usually occurs about 5 to 6 years before the blood sugar 
starts to rise. Cholesterol levels also change: high-density lipoprotein (HDL) 
levels decrease; low-density lipoprotein (LDL) levels (the "bad" type of 
cholesterol), increase. One diabetes prevention trial described by Dr. Cheatham 
will follow 4,000 individuals who have a risk for developing diabetes over a 
7-year period. Fifty percent of study participants will be people of color.

Dr. Cheatham also presented an overview of the evolution of treatments (oral 
pharmaceuticals and insulins) to reduce glucose levels. In the 1940s, sulfonyl 
compounds, when taken orally, lowered glucose levels. Commercially available 
sulfonylureas became available in the 1950s, oral biguandides were discovered in 
the 1960s. By the 1970s, experiments were underway to premix fast and slow 
acting insulins to achieve the benefits of both in one preparation. In the 1980s 
insulin with the same amino acid structure as human insulin was introduced, 
followed by a second generation of sulfonylureas. In the 1990s, a third 
generation of sulfonylureas has been introduced, along with a new biguanide, and 
an alpha-glucosidase inhibitor. Other oral agents are "just around the corner," 
pending final evaluations.

Prostate Cancer

**Dr. Judd Moul** (Uniformed Services University of Health 
Sciences) explained that prostate cancer is now the most common cancer in 
American men. Between 1995 and 1996 new cases have increased by 30 percent. In 
1996, more than 317,000 cases will be diagnosed; more than 41,000 men will die 
from the disease. Because many African-American men are unaware of their high 
risk for prostate cancer and lack access to cancer screening tests, they remain 
undiagnosed for a longer time than white men and consequently have more advanced 
prostate cancer at the time of diagnosis. As a result, the chance for long-term 
survival is lower for African-American men than for white men.

Screening/Treatment Strategies

Dr. Moul reviewed recent advances in prostate cancer treatment of benefit to 
African-American men. Preventive measures include the development of the 
prostate specific antigen (PSA) blood test and new screening guidelines for 
African-American men. These guidelines resulted from a study of 5,000 men in 
U.S. Armed Forces. In this study, the PSA performed differently for African 
American men than for white men. African Americans with prostate cancer were 
about 2 years younger than white men, but had 1.3 to 2.5 times the tumor volume. 
Dr. Moul reported that the new guidelines recommend that (1) African-American 
men be screened beginning at age 40 and (2) the PSA "normal" range for 
African-American men be lowered to "2."  Dr. Moul noted, however, that 
there is still no clear evidence that these preventive measures will be 
effective. More clinical trials are needed. Without this data, it is unlikely 
that managed care organizations will pay for PSA screenings.

Dr. Moul also reviewed other tests and therapies in development for prostate 
cancer:

- Free-PSA, RT-PCR for occult metastasis. Most PSA in bloodstream is bound 
  to other proteins (bound PSA), but about 10 to 20 percent is "free."  The 
  lower the percentage of free PSA, the higher the probability for prostate 
  cancer. However, the free-PSA test has not yet been approved by FDA.

- Surgical treatment (nerve-sparing radical prostatectomy). More African 
  Americans are receiving this treatment, but the outcome is not as good as for 
  white men. Treatment needs to occur earlier, when the cancer is smaller.

- Radiation treatment. In one type of radiation therapy, computers are used 
  to localize the radiation beam; in another type of treatment, irradiated seeds 
  are implanted in the prostate.

- Cryotherapy. Liquid nitrogen is pumped into the prostate to freeze the 
  tumor. (Clinical trials are needed to determine long-term results.)

- "Watchful waiting" after a PSA test. Most of the current data is from 
  white patients. For patients with low [Gleason] grade cancer, the outcome is 
  good, but only 10-15 percent of patients have low grade prostate cancer at 
  diagnosis. A new study, "PIVOT" is being conducted primarily in Veterans 
  Administration sites, which is randomizing men to radical prostatectomy versus 
  watchful waiting. The study is currently undergoing patient accrual.

- Watchful waiting is also the strategy to be used for benign prostatic 
  hyperplasia (BPH). BPH is the noncancerous enlargement of the prostate and 
  occurs in about 80 percent of men over age 50. BPH and prostate cancer are not 
  necessarily linked, but men with BPH should be screened with PSA and a digital 
  rectal exam.

- Hormonal therapy. This is used for a few months prior to surgery, 
  radiation, or cryotherapy, to treat patients with metastatic prostate cancer. 
  The goals are to decrease tumor size and increase long-term survival. Most 
  patients respond for a while, but when they fail hormonal therapy, their 
  options are limited. Clinical trials are urgently needed to develop new 
  treatments for this type of prostate cancer.

Dr. Moul reported that the optimum treatment for prostate cancer is still 
unknown. Men of color are needed for clinical trials of diagnostic tools, new 
local treatments, and new hormonal and chemotherapy agents. To this end, more 
efforts must be made to increase awareness about prostate cancer among 
African-American men and encourage screening. Barriers to early 
detection--distrust, fear of cancer, reluctance to undergo a digital rectal exam 
--must also be overcome.

Finally, Dr. Moul observed that prostate cancer research is at least a decade 
behind that for breast cancer. More research funds are needed. He noted that the 
United States has "spent less on prostate cancer research than on a single jet 
fighter."

Panel: Diverse Perspectives of Clinical 
Trials

Moderator: Linda Ann Sherman, M.D.Panelists: FDA,--Jonca Bull, M.D., 
F.A.A.O.Human Subject Protection--Warren Ashe, 
Ph.D.Patient--Gregory HutchingsCommunity--Otis 
Brawley, 
M.D.Academia--Wayne Greaves, M.D., 
F.A.C.P.Industry--James Powell, 
M.D.

FDA Prespective

**Dr. Jonca Bull** (FDA) presented an overview of FDA's drug 
approval process. First, she noted that the agency's mission is to enforce 
Federal law and FDA regulations to protect the consumer's "health, safety, and 
pocketbook." She then offered an historical perspective of drug regulation in 
the United States and reviewed FDA's growing consumer protection 
responsibilities. Milestones included the passage of the Food, Drug, and 
Cosmetic Act, and the emergence of human subjects protection as a paramount 
agency concern.

She stated that the regulatory function of FDA's Center for Drug Evaluation 
and Research (CDER) is to approve drugs for marketing that (1) are effective for 
their labeled indications, (2) provide benefits that outweigh their risks, and 
(3) have labeling for use that is complete and honestly communicated. She 
distinguished between drugs, biological products (e.g., vaccines, blood 
products), and medical devices. Each is handled somewhat differently in the 
development and approval process.

Dr. Bull then described the process of moving a drug from discovery to the 
marketplace. After a drug is shown to have promise in terms of efficacy and an 
adequate measure of safety for humans, it moves into clinical trials to test for 
effects in humans. Clinical trials are categorized into the following phases:

- Phase I -- Small studies, usually involving 20 to 100 patients, for the 
  purpose of determining safety.

- Phase I -- Larger studies, involving up to several hundred subjects, to 
  further explore safety and to determine effective dosage for a specific 
  indication.

- Phase III -- Still larger studies, involving up to several thousand 
  subjects, for the purpose of assessing safety, efficacy, and dosage and to 
  better characterize the drug for its intended use.

- Phase IV -- Post-approval studies to further characterize the drug. For 
  HIV drugs, which are approved on the basis of surrogate markers (e.g., CD4 
  counts, changes in viral load), these studies are intended to document the 
  drug's clinical benefit. If the drug shows no clinical benefit, the sponsor is 
  required to voluntarily withdraw the drug from the market. Phase IV trials 
  also enable sponsors to evaluate the drug in populations that may not have 
  been well represented in the Phase III trials.

Next, Dr. Bull explained FDA mechanisms for evaluating promising new drugs: 
Investigational New Drug applications (INDs), New Drug Applications (NDAs), and 
Abbreviated New Drug Application (ANDAs). An investigational drug is a drug that 
has not been approved for use in human subjects. The drug sponsor is required to 
submit an IND application, which contains an exemption permitting the drug to be 
studied in humans. The FDA has a 30-day time limit to review the application and 
either grant or withhold an exemption.

After the IND is allowed to proceed, the sponsor moves the drug into clinical 
research trials (Phases I, II, and III). This process culminates in the 
preparation of an NDA, for the purpose of marketing the new drug. Dr. Bull 
explained that the NDA usually involves thousands of pages, and includes 
chemistry, pharmacology, toxicology, and other sections. The NDA is intended to 
provide clinical guidance for the optimum use of the drug for a specified 
indication. The package insert that accompanies the marketed drug includes a 
description of the product information on dosage and administration, 
contra-indications, adverse reactions, etc.

When evaluating a drug, FDA seeks to determine that the drug has been tested 
in patients who are similar in demographics to the group who will be using the 
drug. FDA also ensures that efficacy and safety have been assessed. In addition, 
FDA assesses:

- Drug-demographic interactions to identify demographic features that could 
  alter the metabolism or distribution of the drug or be associated with altered 
  efficacy or adverse events; and

- Drug-disease interactions to identify disease features that could alter 
  the metabolism or distribution of the drug, or be associated with more 
  frequent or more severe adverse events.

Dr. Bull noted that FDA's regulatory function does not stop with drug 
approval. She described FDA's MedWatch Program, which enables side effects to be 
reported after the drug has entered the market. (The MedWatch program is 
accessed through a toll-free number and reports are handled with strict 
confidentiality.) If problems arise, FDA can issue "Dear Health Professional" 
letters to alert physicians, change product labeling or packaging, or institute 
a product recall or withdrawal.

Human Subjects Protection

**Dr. Warren Ashe** (Howard University College of Medicine) 
spoke about the issue of protecting subjects who participate in clinical trials. 
The primary mechanism for this is the Institutional Review Board (IRB), which is 
established by the institution conducting the study and is responsible for 
reviewing all protocols that involve human subjects. IRBs are composed of 
community representatives, nonscientists, and ethicists.

During his discussion of the origins and history of IRBs, Dr. Ashe noted that 
outrage over the Tuskeegee Syphilis study marked the beginning of this country's 
sensitivity to human subjects protection. Dr. Ashe reviewed the regulations that 
led to the establishment and refinement of the IRB process, noting that the 
"challenge is to make sure that every individual is protected." This means 
establishing procedures so that "informed consent is indeed informed consent and 
not an inducement or a coercion to participate in a research program."

Dr. Ashe acknowledged, however, that concerns remain among subjects who are 
recruited to participate in clinical trials. Therefore, the success of 
recruiting women and minorities in clinical trials depends on several factors. 
These are outlined below.

- Recruitment procedures must be carefully considered. Dr. Ashe suggested 
  that recruiters "come from the community." He cautioned against having 
  recruiters "show up in a white coat" because it can be extremely intimidating 
  for prospective study subjects.

- Methods for obtaining informed consent must clearly explain the purpose of 
  a clinical trial to prospective study subjects. Subjects must be assured that 
  they can withdraw at any time from the trial without any penalty.

- Study subjects should be told about risks and benefits of participation. 
  Possible side effects should be described in lay terminology.

- Study subjects must be confident that any new, beneficial information 
  about treatment developed during the trial will be available, even if it means 
  that they stop participating in the trial.

- Study investigators should "use language that people can understand" and 
  make it appropriate to an eighth grade reading level.

- Compensation for participation must be commensurate with the risk; 
  otherwise, the compensation could be construed as an inducement that would 
  compromise true informed consent.

- The IRB needs to monitor the trial to ensure that protocol is being 
  followed.

Other considerations for the development of informed consent protocols 
include the following:

- Informed consent should include a comprehensive discussion about what is 
  currently known about the drug and any possible long-term limitations. For 
  example, taking the study drug might preclude taking other therapies at a 
  later time. In the case of protease inhibitors, the patient should be aware of 
  the enormous expense of continuing the drug once the study ends.

- The study description should be written in lay language and can be as 
  extensive as the investigator wishes. It could include background information 
  describing why the study is being conducted, and a section describing what the 
  expected outcomes are. One drawback, however, is that the consent form can 
  become too lengthy. The impetus for informed consent would still require that 
  the investigator and patient "plow through it." If necessary, the investigator 
  should review the form repeatedly until the patient fully understands its 
  content and implications.

Patient Perspective

**Mr. Gregory Hutchings** (D.C. Agency for HIV/AIDS) offered his 
perspective, as an HIV-positive African American who had participated in several 
HIV drug treatment trials. He suggested that people wanting to participate in 
clinical trials "find out exactly what is happening" in the clinical trial, in 
terms of type of medication, dosage regimen, side effects, etc. He suggested 
talking to other people who have taken the drug and reading any available 
literature about the drug.

He commented that he, like many African Americans, is very cautious when it 
comes to participating in clinical trials for experimental drugs; consequently, 
he prefers to enroll in trials of already approved drugs. Mr. Hutchings observed 
that many patients are unaware of the many trials being conducted with 
nonexperimental drugs. He recommended that investigators offer patients an 
opportunity to enroll in these studies of nonexperimental agents, noting that 
"it's a good **in** for getting people involved [in their first 
clinical trial] and gaining their trust."

Other strategies suggested for building trust with prospective study subjects 
and facilitating trial enrollment are noted below:

- Have "culturally competent" staff administer the trials.

- Make patients feel as comfortable as possible and convey that "you're not 
  this person of authority who is...enticing them into doing something that they 
  don't want to do." Make it clear to patients that they can choose not to 
  participate.

- Ensure that written materials are "reader accessible."

- Let patients know that there are other patients, from the same ethnic 
  background, who are participating in the trial.

- Use nontraditional methods to recruit patients. Design the trial 
  enrollment announcement so that it "gears that person to wanting the 
  information, to want to get involved . . ."  In addition to posting 
  notices on bulletin boards or in the newspaper, "get out and talk about it."

- Suggest that the patient's private physician also monitor for drug 
  effects.

Mr. Hutchings observed that even the **perception**of unethical 
behavior on the part of clinical trial organizers can damage chances for 
recruiting people of color. He added that the "only way we can involve community 
members in participating in clinical trials is to be able to explain how 
[Tuskeegee syphilis study] can't happen again."

Community Perspective

**Dr. Otis Brawley**, National Cancer Institute (NCI), spoke 
about clinical trials programs sponsored by NCI. First he noted that only about 
3 percent of cancer patients participate in clinical trials. To increase patient 
access to trials, NCI sponsors ten cooperative groups involving nearly 500 
academic and community hospitals that run cancer-related clinical trials. These 
groups accrue nearly 30,000 patients annually to cancer treatment trials and 
nearly 20,000 healthy people to cancer control studies (i.e., primarily 
screening and prevention studies).

Minority-Based Community Clinical Oncology Program

In 1990, NCI established its Minority-Based Community Clinical Oncology 
Program (MB-CCOP). The program funds groups of physicians and hospitals that 
care for large numbers of minority patients for the purpose of enrolling 
minority patients into NCI clinical trials. Between 1991 and 1994, about 14 
percent of patients in NCI cooperative group and cancer center trials 
self-identified as a minority. Ten MB-CCOPs accrued about 10 percent of all 
minority patients entering NCI-sponsored treatment trials during this period. 
The MB-CCOPs maintains a log of all newly diagnosed cancer patients seen by the 
centers. (This log is expected to provide important insights into the dynamics 
of minority patient accrual.)

NCI-Sponsored Cancer Treatment Trials

Dr. Brawley described studies to determine the extent to which African 
Americans and Hispanics participate in NCI-sponsored treatment trials. The first 
study analyzed demographic data from 7,809 newly diagnosed adult patients seen 
at 12 MB-CCOP sites. Enrollment rates for whites, Hispanics, and African 
Americans were similar. Of 820 patients eligible to enroll in a trial, 62 
percent of the whites, 70 percent of the Hispanics, and 61 percent of the 
African-American patients enrolled. Dr. Brawley believed this demonstrates that 
hospitals that have a good relationship with their communities can enroll 
Hispanics and African Americans at rates similar to whites.

Another study described by Dr. Brawley examined data from nearly 100,000 
patients accrued to NCI-sponsored cooperative group trials between 1992 and 
1994. These data also showed African-American, white, and Hispanic patients to 
be proportionally represented. Indeed, in some cases African Americans and 
Hispanics are overrepresented. For example, 10.3 percent of men with prostate 
cancer are African-American, but 14.7 percent of men in NCI prostate cancer 
studies are African American. Similarly, 4.8 percent of leukemia patients are 
Hispanic, but 9.5 percent of patients in NCI leukemia trials are Hispanic.

NCI-Sponsored Cancer Prevention Studies

Dr. Brawley observed that although NCI cooperative group accrues large 
numbers of minority patients to treatment trials, it is unable to achieve 
similar success for prevention and control trials. For example, in NCIs Prostate 
Cancer Prevention Trial (which is being managed by an African-American 
physician) only 4 percent of the 18,000 subjects are African American and only 
three percent are Hispanic.

Dr. Brawley suggested that the reasons for the disparity in ethnic enrollment 
patterns could be related to the following. Prevention studies (i.e., studies of 
healthy people) attract the individuals who are highly educated and economically 
secure. In the prostate prevention trial, for example, 37 percent of all 18,000 
enrollees had a post-baccalaureate degree, compared with 31 percent of 900 
African-American enrollees. Dr. Brawley observed that the people who participate 
in prevention studies "can afford to take time off from work twice a year to go 
to the doctor for a problem they do not have."

Dr. Brawley noted that some people have called for proportional 
representation in clinical trials, assuming that proportional representation 
allows for an analysis to determine if one intervention is more effective in one 
population than another. He cautioned that proportional representation rarely 
provides statistical power needed to reach any firm conclusions. He added that, 
fortunately, clinically relevant differences among different ethnic populations 
are likely to be rare. It was also noted that the ease or difficulty in 
recruiting depends a great deal on the expectations for the product being 
studied in the trial.

Academia's Perspective

**Dr. Wayne Greaves** (Howard University College of Medicine) 
shared his perspective as a clinical investigator for an academic center. Dr. 
Greaves began by observing that academic centers continue to play an important 
part in the conduct of clinical trials, and they offer unique opportunities for 
teaching and patient care. He also noted that patients who participate in 
clinical trials have several advantages; specifically, free care, flexible 
appointment schedules, access to new treatments, and access to experts in the 
field.

Challenges Faced by Investigators at Academic Institutions

Dr. Greaves noted, however, that investigators in academia face many 
challenges. First, they must meet exacting scientific and regulatory standards. 
Careful recordkeeping is a key part of this challenge. Second, they must recruit 
research subjects from a population that is increasingly skeptical of research. 
Third, investigators at academic centers face intense competition from (1) 
organizations that can offer incentives (e.g., free care) previously available 
only in the academic setting and (2) for-profit research organizations that are 
often able to outperform academic centers in conducting clinical trials. All 
this results in greater competition for the research dollar.

A related issue is that minority institutions find it difficult to compete 
with "Ivy League" institutions for research grants from the pharmaceutical 
industry. Dr. Greaves observed that if drug companies believe they can get their 
products to market "faster through Johns Hopkins or Yale, then that's what 
they'll do." During the discussion period, it was also noted that pharmaceutical 
companies often "try to take advantage of the naivete" of minority institutions 
like Howard by offering them less funds than they would offer Ivy League 
institutions to conduct similar research.

In addition to these challenges, the academic researcher also has heavy 
clinical and teaching obligations that have to be coordinated with the research 
activity. Another pressure for academic investigators is the need to "publish or 
perish."   "Town vs. gown" tension represents another challenge to 
overcome. To facilitate clinical trial referrals, it is essential that academic 
investigators build good relationships with physicians in the community.

Other challenges include the following:

- Protocol approval by the IRB is often protracted.

- Remuneration is made directly to institution.

- The study outcome is unknown for years.

Barriers to the Participation of Minority Academic Institutions

Dr. Greaves also commented on several barriers that prevent minority academic 
institutions from participating in clinical research. Traditionally, the 
emphasis is on teaching and the provision of care; research is less of a 
priority. Another barrier is that becoming a research center requires enormous 
financial resources, which minority institutions seldom have. Yet another 
barrier is that physicians at minority institutions may not be as interested in 
referring patients to trials for an experimental therapy as they are in 
providing their patients with good care. Therefore, it is not surprising that 
researchers at Howard University, for example, have had "a fairly difficult time 
recruiting patients for our clinical trials, even though we are a minority 
institution, and even though we are minority investigators."

Qualities of a Successful Clinical Investigator

Dr. Greaves offered the following observations about the qualities of a 
successful clinical investigator. The successful investigator is one who is 
knowledgeable about clinical trials, motivated, plans ahead, develops a trained 
research team, hires skilled administrative staff, clarifies the role and 
obligations of the study sponsor, and involves patients in study implementation. 
Knowledge of administrative and budgetary aspects of clinical trials are also 
critical to ensure smooth study implementation.

Successful clinical investigators also need to handle the following 
logistical issues:

- Recruiting qualified personnel; training and supervising staff; and 
  conducting periodic reviews of staff

- Establishing and managing the budget

- Working closely with the IRB

- Recruiting study subjects and communicating with referring physicians

- Holding regular meetings with the study team

Also key to an investigator's success is avoiding the potential pitfalls that 
characterize clinical trial management. Pitfalls include:

- Not clearly explaining informed consent

- Signing documents before reading them

- Hiring unqualified personnel

- Not reading protocol carefully

- Not reporting adverse events promptly

- Conducting too many studies at once

- Over delegating work/not supervising closely

- Improperly administering the budget

Recruitment Challenges for HIV Trials

During his presentation, Dr. Greaves also discussed the difficulty recruiting 
people of color for HIV clinical trials. HIV is characterized by many sensitive 
ethnic and lifestyle issues. For example, some patients find it difficult to 
acknowledge their seropositive status. In addition, there are few HIV activists 
in communities of color, as compared with white gay communities. In addition, 
HIV patients are frequently on many medications, and adverse drug interactions 
are common. Moreover the "gold standard keeps shifting," for example, from AZT 
monotherapy to combination therapy. This makes it hard to recruit and retain 
patients in long-term trials.

Industry Perspective

**Dr. James Powell** (Proctor and Gamble) discussed how the 
pharmaceutical industry selects investigators for its clinical trials. First, 
Dr. Powell noted that the involvement of primary care physicians is key to 
maximizing the quality of care available to patients and urged symposium 
attendees to participate in the drug development process as clinical trial 
investigators. Dr. Powell reviewed sponsor's expectations of the clinical 
investigator, discussed the potential benefits and rewards, and examined 
strategies to expand opportunities for those interested in becoming an 
investigator for industry-sponsored trials.

He stated that the discovery, development, manufacture, and marketing of new 
pharmaceutical products is a complex, multidisciplinary process. The complexity 
derives from the array of laboratory and manufacturing controls required and the 
need for data from human and other sources to support the product's proper, 
safe, and effective use.

From the industry's perspective, the factors that drive drug development are 
regulations, time, and cost. Regulatory drivers include good clinical practices 
(GCP) guidelines that ensure a basic level of quality in the conduct of the 
trials and the data obtained. Other regulations require that drug sponsors prove 
the safety and effectiveness of their products and that they have enrolled 
subjects that reflect the target population. To meet these requirements, drug 
sponsors design protocols to collect the necessary data, often with input from 
the regulatory authorities.

Data generated by the clinical trial are property of the drug sponsor. Often 
sponsors also seek to have the final rights on any publications that might 
result from the trial.

Other factors that drive drug development are cost and time. It costs about 
$500 million to bring a new drug to the marketplace (through Phase III trials). 
The time from drug discovery/concept to the marketplace is at least 10 years. 
Excluding patent extensions, the drug sponsor has about 7 years to recoup its 
investment in the marketplace. The revenue loss that occurs when a patent 
expires and the beginning of competition from generic brands "makes timing a 
matter of survival for the industry." In fact, noted Dr. Powell, "time is not 
just money; time is more important than money."

Dr. Powell elaborated on the regulatory requirement that the investigator be 
qualified in terms of training and experience. The "ideal" investigator:

- Meets requirements for training and experience

- Has the time, resources, and staff to conduct the study

- Complies with regulatory requirements and adheres to the study protocol

- Knows the target patient population and demonstrates the ability to 
  recruit subjects

- Understands the sponsor's priorities and intent

- Delivers the data on schedule and communicates issues in a timely manner

- Has experience with the type of study being undertaken

Dr. Powell reviewed the benefits to investigators who undertake a clinical 
trial: access to new therapies, considerable financial return, site development 
support (e.g., new equipment, staff), and publication opportunities.

Dr. Powell discussed a strategy used by drug sponsors in need of "instant" 
organizational capacity. Instead of contracting with a single investigator, the 
drug company links with a contract research organization (CRO). In the CRO 
arrangement, the sponsor carries the staffing cost only for the time needed to 
conduct the trial. CROs are selected for their experience with the type of 
study, access to qualified investigators, focus on "getting the job done," and 
awareness of regulatory issues.

Dr. Powell suggested that symposium participants who wished to establish 
themselves as clinical trial investigators demonstrate "interest, capability, 
and access." For example, become a "sub-investigator" for a study being 
conducted by a local hospital or academic center. This provides an opportunity 
to (1) become familiar with the extensive documentation required for clinical 
trials and (2) gain a working knowledge of GCP requirements. Dr. Powell also 
suggested that prospective investigators contact the drug sponsor or CRO 
directly.

Dr. Powell stated that FDA and PHARMA have held some discussions about 
improving minority/investigator recruitment. He noted that the pharmaceutical 
industry is required to include representation of the target population in its 
studies. He observed that industry collaborations with the "usual" academic 
sites may not allow investigators to obtain broader access to minority study 
subjects. It was also noted by Dr. Bull that representation should be relevant 
in terms of disease prevalence among the target population, in addition to 
demographically relevant.

Panel: Expanded Access Mechanisms 
and Managing Costs of Clinical Trials and Investigational Therapies

Moderator: Theresa Toigo, R.Ph., M.B.A.Panelists: Expanded 
Access--Heidi Jolson, M.D., 
M.P.H.AIDS Drug Assistance--Steven Young, 
M.P.H.Managed Care--Mary McCabe, 
R.N.Medicaid/Medicare--Gerald Zelinger, 
M.D.

Expanded Access

**Dr. Heidi Jolson** (FDA) focused on the concept of "expanded 
access" and the regulatory mechanisms developed by FDA to expedite the 
availability, development, evaluation, and marketing of new therapies. Dr. 
Jolson explained that these mechanisms are intended to make investigational 
therapies available to people with serious or life-threatening illnesses and 
without other treatment options, before the therapies receive approval from FDA. 
In addition to enhancing access to promising new therapies, the expanded access 
mechanisms provide important information on a drug's safety and efficacy -- 
without compromising the patient's safety and the integrity of the clinical 
trial evaluation.

Dr. Jolson pointed out that the expanded access procedures reflect FDA's 
recognition that physicians and patients are generally willing to accept greater 
risk or side effects to treat life-threatening illnesses.

Although the primary objective is patient treatment, FDA encourages drug 
sponsors to design the programs in such a way as to obtain meaningful data that 
can be collected to further knowledge about the drug. All of the expanded access 
programs share common features: They are "open label;" that is, physicians and 
patients alike know what drug the patient is receiving. In most cases patients 
in the program only have one choice of drug, although occasionally different 
groups of patients take different doses of the drug, allowing for dose 
comparisons. Drugs used in the program must have demonstrated a degree of 
efficacy, either in vitro or in clinical studies.

Dr. Jolson explained the five mechanisms for expanded access. These are 
summarized below.

**Group C Drugs**This is a mechanism specifically for the 
development of cancer therapies and represents a collaboration between the 
National Cancer Institute and FDA.

**Emergency Investigational New Drug (E-IND)**In this 
mechanism a physician calls FDA and/or the pharmaceutical company directly and 
requests that the investigational drug be made available to a specific patient. 
The drug manufacturer must also be contacted to initiate shipment of the drug. 
In this type of emergency situation, a written submission is unnecessary; 
however, FDA expects the physician to submit an IND application as soon as 
possible. In 1995, 624 E-INDs were issued by FDA's Division of Antiviral Drug 
Products.

**Open Label Protocol** This is the most commonly used 
expanded access mechanism and used if a physician or pharmaceutical company 
expects to request a drug for multiple patients. FDA prefers that the sponsor 
develop a treatment protocol, instead of contacting FDA on a patient-by-patient 
basis. The open label for 3TC, a promising AIDS drug, enrolled over 32,000 
patients and involved about 1,400 investigators before the drug was approved for 
marketing. One drawback to this mechanism is that drug sponsors seldom 
manufacture large quantities of a drug prior to its final approval by FDA.

**Treatment IND (T-IND)** This mechanism is similar to the 
open label protocol, except that the T-IND occurs later in drug development. It 
is meant to bridge the time between when controlled clinical trials are almost 
complete and the new drug application is approved. The T-IND protocol needs to 
include: intended use, patient eligibility criteria, route and dose information, 
safety monitoring reports, and the investigator's brochure. Compliance with the 
patient safeguard processes must also be demonstrated (e.g., informed consent). 
Between June 1987 and September 1996, 38 Treatment INDs were granted: 13 cancer 
drugs, 11 HIV drugs and the remaining 14 for a variety of other serious and 
life-threatening diseases.  All of these drugs were eventually approved by 
the FDA.

**Parallel Track**This mechanism was established in 1992 
specifically for HIV therapies and provides patients with access to new 
therapies very early in the drug development process. Under this mechanism, 
expanded access is provided in parallel (i.e., concurrently) with clinical trial 
investigations. The mechanism is fairly cumbersome, in that it requires 
coordination between the National Institutes of Health and FDA. Thus far, it has 
only been used once, for d4T (Stavudine). The mechanism provides explicit 
criteria to protect patients and the clinical trials process.

To demonstrate the effectiveness of the expanded access programs, Dr. Jolson 
presented a chart with information about HIV therapeutics. To date, more than 
80,000 HIV-positive patients have received antiretroviral therapies prior to FDA 
approval. The data indicated that the enrollment of women has improved slightly 
since 1986 and that minority enrollment has been consistently about 20 percent.

AIDS Drug Assistance

**Steven Young**, Health Resources and Services Administration, 
discussed provisions of the Ryan White Comprehensive AIDS Resources Emergency 
(CARE) Act that provide ways to expand patient access to investigational 
therapies. The Care Act offers nearly $1 billion in funding to help communities 
respond to the needs of people with HIV. Title I of the CARE Act provides funds 
to cities and metropolitan areas especially hard hit by the HIV epidemic. The 
Title I funding formula is based on the number of residents who are living with 
HIV and its purpose is to provide financial relief for services that have no 
other source of payment. Supplemental funds can be granted, depending on the 
needs of special populations (e.g., people of color, homeless, substance 
abusers, etc.) within that metropolitan area. Currently, 49 Emergency 
Metropolitan Areas (EMAs) receive funds. Funds are used for a broad range of 
outpatient health care services (e.g., medical, dental, substance abuse).

Title II of the CARE Act provides funds directly to the states to improve the 
quality and availability of primary care services. Under Title II, the states 
determine how the funds are to be channeled: through HIV care consortia, home 
and community-based care, health insurance reimbursement, or AIDS drug 
reimbursement.

AIDS Drug Assistance Program

Mr. Young explained that the CARE Act provides approximately $220 million for 
the AIDS Drug Assistance Program (ADAP). In 1995 the ADAP program served nearly 
70,000 patients: 41 percent were white, 29 percent were African American, and 28 
percent were Hispanic. ADAP provides reimbursement for FDA-approved drugs that 
treat HIV or prevent the serious deterioration of health caused by HIV. The 
program also reimburses for ancillary devices (e.g., tubing, nebulizers). The 
formularies for reimbursement are established by each state and, therefore, can 
vary widely. Mr. Young cautioned that many states are placing reimbursement caps 
on their programs, because they lack the financial resources to pay for the new, 
highly effective -- and expensive -- AIDS drugs (i.e., protease inhibitors).

Outreach to Improve Patient Access to Investigational HIV Drugs

Title I and Title II funds may **not** be used to support the 
costs of conducting clinical trials, including administrative costs and patient 
monitoring. However, the funds can be used to conduct patient outreach to 
promote enrollment in clinical trials and expanded access programs. The funds 
can also be used to reimburse for complementary (i.e., alternative) therapies. 
Mr. Young cautioned against using the term "alternative" because it elicits "a 
very bad reaction from politicians and budget folks" who see it as a "way around 
the system." He noted that most people, however, understand the need to 
complement the traditional medical approach.

Mr. Young also described other CARE Act provisions to expand patients' access 
to investigational therapies. The CARE Act provides funding support for:

- Clinical trials volunteer networks. For example, the D.C. HIV Care 
  Consortium provides "dual" referrals, linking community providers with 
  clinical trial investigators and vice versa.

- Targeted outreach. Several cities and states operate computer databases 
  that list all the clinical trials in the area and patients that want to 
  volunteer for clinical trials.

- Public information campaigns (brochures, radio advertisements, posters, 
  etc.).

- Case managers are supported in their efforts to develop formal 
  relationships with local clinical trial programs and facilitate patient 
  referrals to these trials.

- Primary care physicians are supported for participation in expanded access 
  or compassionate use programs.

Finally, Mr. Young discussed Title IV, which focuses on women, children, and 
families with HIV. Grants are now being offered under this Title to increase the 
participation of women and children in clinical trials. Another provision in 
Title IV relates to improved coordination between the National Institutes of 
Health and HRSA.

Managed Care

**Mary McCabe** (National Cancer Institute) reviewed the impact 
of the "managed care" service delivery and reimbursement system on the conduct 
of clinical cancer research. She stated that financial support for this research 
previously had been shared by the Federal Government, pharmaceutical industry, 
private institutions, and third party payers.

There is now, however, widespread uncertainty about future support for 
clinical research, chiefly because the managed care system is driven by economic 
incentives and will not support the costs of caring for patients who are 
receiving experimental therapies. As managed care systems proliferate, cancer 
patients and health professionals are also voicing concerns about the future 
quality of cancer treatment and continued access to promising therapies through 
clinical trials. This has particularly important implications for communities of 
color because minority access to clinical trials is closely linked with the 
provision of quality health care.

The changes in clinical trial coverage brought about by managed care are 
noted below:

- Reduced financial incentives. These result in fewer referral opportunities 
  for patients, limited reimbursement to participating physicians, and less 
  interest in developing answers to research questions.

- Constraints on physicians practices. Investigators lack the time and 
  resources to participate in clinical trials. For example, how does a physician 
  ensure a patient's informed consent when the time to explain the trial is 
  limited.

- Constraints on institutions. Traditional referral networks are disrupted, 
  making it harder to for physicians to refer patients to the academic center or 
  hospital that is conducting a specific trial.

- Limited access for patients. Underinsured/uninsured patients have fewer 
  opportunities to access trials. Patients have limited out-of-plan referral 
  options, uneven benefits, and inconsistent coverage.

Ms. McCabe reviewed current NCI initiatives to address the issues raised by 
managed care. These include agreements between NCI and managed care 
organizations. The Department of Defense, for example, has agreed to cover 
participation of CHAMPUS members in NCI-sponsored treatment trials. The Veterans 
Administration has entered into an even broader agreement that will cover 
participation in NCI prevention trials. The Blue Cross/Blue Shield's Pediatric 
Cancer Network has agreed to ensure clinical trial access for children covered 
under these plans.

Other NCI initiatives includes linkages with the HMO Research Network, which 
serves a large minority population, regional Cancer Center networks, and the 
development of Federal and State legislation to provide coverage for 
cancer-related clinical trials.

Ms. McCabe concluded by offering the following recommendations for ensuring 
expanding patient access to clinical trials:

- Increase public awareness regarding the importance of clinical research 
  and patient access to clinical trial participation.

- Encourage physicians to enroll patients in trials, despite the financial 
  disincentives.

- Conduct more efficient, more economical clinical trials that conform as 
  much as possible to the standard of care.

- Incorporate more endpoints of interest -- to patients and third-party 
  payers-- into clinical trial protocols (e.g., cost-effectiveness and other 
  economic endpoints; quality of life and functional improvement endpoints).

Medicaid/Medicare

**Dr. Gerald Zelinger**, Health Care Financing Administration 
(HCFA), stated that in recent years, Medicare and Medicaid, the two publicly 
financed health care programs administered by HCFA, have expanded their coverage 
of investigational and experimental therapies and procedures.

Medicare

Dr. Zelinger explained that Medicare covers people age 65 and older, those of 
any age who are disabled, and those of any age with end stage renal disease. The 
Social Security Act (Title 18) states that Medicare can cover only "reasonable 
and necessary" items and services. The traditional interpretation of this 
statutory language is an assessment of whether a therapy is safe and effective, 
medically appropriate, not investigational or experimental, and not excluded 
from coverage by the Social Security Act.

Dr. Zelinger acknowledged that what is considered investigational or 
experimental often "resides in the beliefs of the person or agency you are 
talking to." Recently HCFA has been expanding its Medicare coverage of new 
medical technologies, transplant procedures, and drugs. For example, 90 percent 
of kidney transplants are covered. Medicare will cover FDA approved drugs for 
their labeled indications; off-label indications are left to the discretion of 
the Medicare contractor. HIV antiretrovirals (e.g., FDA-approved protease 
inhibitors) and self-administered drugs (e.g., oral prescription drugs) are not 
covered.

He noted that HCFA is in the process of developing a final rule regarding how 
coverage determinations will be made. This is expected to be published in late 
1997. The final rule may include considerations for covering Treatment INDs.

Medicaid

The statutory basis for this program is Title 19 of the Social Security Act. 
The program pays for medical services for certain groups of low-income 
individuals (i.e., disabled, aged, blind, pregnant women, children, and single 
parents). Dr. Zelinger noted that neither the Medicaid statute or regulations 
discuss or define investigational therapies. Medical necessity is only briefly 
mentioned in regulation.

Medicaid is a joint Federal/State entitlement program, but each state has 
considerable discretion in implementing its own program. States have flexibility 
in determining what is considered investigational, experimental, or medically 
necessary. Even when a state determines that a procedure is investigational or 
experimental, the state may still decide to cover it. For example, HIV viral 
load tests were covered prior to their approval by FDA.

Under the Medicaid Drug Rebate Act of 1991, States are required to cover all 
FDA-approved drugs of manufacturers who have signed an agreement with FDA. Thus, 
Medicaid, unlike Medicare, covers FDA-approved antiretrovirals.

Medicaid and Managed Care

Approximately one-third of Medicaid beneficiaries are enrolled in managed 
care plans, compared with 12 percent of Medicare beneficiaries. Because Medicaid 
managed care plans are bound by their contracts with the States, they may not 
use formularies to determine drug coverage. Recently, HCFA has begun to inform 
its managed care plans that they must cover drugs that would be available to 
Medicaid patients in the fee-for-service setting. Thus, for example, Medicaid 
managed care plans must cover antiretrovirals like the protease inhibitors.

Dr. Zelinger echoed Ms. McCabe's assessment of the difficulty in getting 
managed care to participate in clinical trials, chiefly because the plans are 
unwilling to "lose control" of their patients and patient care costs. He 
observed that it may be unfair for managed care plans to benefit from clinical 
trials without having to participate in some way. Nonparticipation also deprives 
managed care patients from receiving treatments early on.

Adjournment

* * * *

APPENDIX 1

Symposium Faculty

Warren K. Ashe, Ph.D.Associate Dean for Research, Howard University 
College of Medicine, Washington, D.C.

Otis W. Brawley, M.D.Director, Office of Special Populations, National 
Cancer Institute, Bethesda, MD.

Jonca C. Bull, M.D., F.A.A.O.Medical Officer, Division of 
Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products, Center for Drug 
Evaluation and Research, Food and Drug Administration, Rockville, MD.

Wayman W. Cheatham, M.D.Assistant Professor of Medicine, Howard 
University College of Medicine, Washington, D.C.

David W. Feigal, Jr., M.D., M.P.H.Acting Director, Office of 
Antimicrobial Drug EvaluationDirector, Division of Antiviral Drug 
ProductsCenter for Drug Evaluation and Research, Food and Drug 
Administration, Rockville, MD.

Wayne L. Greaves, M.D., F.A.C.P.Associate Professor of Medicine, Howard 
University College of Medicine, Washington, D.C.

Sharon Smith HolstonDeputy Commissioner for External Affairs, Food and 
Drug Administration, Rockville, MD.

Gregory C. HutchingsPrevention Coordinator, D.C. Agency for HIV/AIDS, 
Washington, D.C.

Heidi M. Jolson, M.D., M.P.H.Medical Officer, Division of Antiviral Drug 
Products, Food and Drug Administration, Rockville, MD.

Celia J. Maxwell, M.D., F.A.C.P.Special Assistant to the Commissioner, 
Food and Drug Administration, Rockville, MD.Assistant Professor of Medicine, 
Howard University College of Medicine, Washington, D.C.

Mary S. McCabe, R.N.Special Assistant to the Director, Division of Cancer 
Treatment Diagnosis, and Centers National Cancer Institute, Bethesda, MD.

Vinod Mody, M.D.Chief, Division of Infectious Diseases, Howard University 
Hospital, Washington, D.C.

Judd W. Moul, M.D., F.A.C.S.Director, Department of Defense Center for 
Prostate Disease Research, Uniformed Services University of the Health Sciences, 
Bethesda, MD.

James H. Powell, M.D.Senior Medical Director, Clinical Pharmacology and 
Pharmacokinetics, Procter and Gamble, Cincinnati, OH.

Otelio S. Randall, M.D., F.A.C.C.Professor of Medicine, Director, General 
Clinical Research Center, Preventive Cardiology/Hypertension Clinical Trials 
Section, Howard University College of Medicine, Washington, D.C.

Linda Ann Sherman, M.D.Special Assistant to the Deputy Commissioner for 
Operations, Food and Drug Administration, Rockville, MD.

Theresa A. Toigo, R.Ph., M.B.A.Associate Commissioner for AIDS and 
Special Health Issues, Food and Drug Administration, Rockville, MD.

Stephen Young, M.P.H.Division of HIV Services, Health Resources and 
Services Administration, Rockville, MD.

Gerald Zelinger, M.D.Medical Advisor, Medicaid Bureau, Health Care 
Financing Administration, Baltimore, MD.

**Symposium Held on October 25, 1996Howard 
University, Washington, DC**

END

KRA Corporation 1010 Wayne AvenueSuite 850Silver Spring, Maryland 
20910December 26, 1996

This document was prepared under Contract Number 277-95-2024 between the 
Howard University College of Medicine in cooperation with Maryland Aids 
Professional Education Center and KRA Corporation of Silver Spring, Maryland. 
The contents of this document do not necessarily reflect the views or policies 
of the Department, nor does mention of trade names, commercial products, or 
organizations imply endorsement by the U.S. Government.

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