National Association of African American Studies National Association of Hispanic and Latino Studies

National Association of Native American Studies International Association of Asian Studies

International Research Forum

Special Guests Universidad Autónoma de Coahuila

April 27-May 1, 2014 Mississippi College Clinton, Mississippi

CLINICAL TRIAL HEALTH DISPARITIES FROM THE MISSISSIPPI

STANDPOINT

JOHN PILETZ, PHD

MISSISSIPPI COLLEGE

CLINTON, MISSISSIPPI

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Clinical Trial Health Disparities from the Mississippi Standpoint

Abstract

Over the past 10 years it has become commonplace that clinical trial data comes largely

from non-US clinics scattered across emerging economies like Brazil, Russia, India, and China.

The shift away from US sites has occurred largely for economic reasons, and though there’s been

little public outcry, there have been red flags. This article explores these red flags in light of the

need for minority racial and ethnic populations before approving new medications in the USA,

and particularly not to overlook Mississippi. The NIH-sponsored Jackson Heart Study was a

notable exception for African Americans in clinical trials, but Mississippians still remain vastly

underrepresented compared to, for instance, US east-coast clinical trial recruitments when it

comes to pharmaceutical trials. To address these issues, in 2011 the author launched a pioneering

business model to manage clinical trials in private practices in Mississippi, which is called the

Embedded Partnership Model. It was advertised that this business model would provide more

clinical trials to minorities in Mississippi. The model brings rewards as well as research rigor to

private practices in community settings, trains the physicians (of any race or ethnicity) in clinical

trials, and lets them become Principal Investigators in full partnership with the company, which

by then is a service provider. Private practices were sought because they are able to streamline

the clinical trial process and therefore become more economically competitive with overseas

sites. This article reports on the first two years of this business. There were struggles both to

change the prevailing mindset of pharmaceutical companies about coming to Mississippi as well

as to gain agreements from minority private practice physicians to enter the clinical trials

business. Nonetheless, it is argued that ultimately Big Pharma would benefit from clinical trials

being run in more sites within the USA like Mississippi.

Introduction

It is no secret that the major pharmaceutical companies, which will be referred to herein

as Big Pharma, currently face diminished returns on research investments. Big Pharma’s pipeline

seems stagnant compared to prior eras [1], and speculation has it there’s been a failure to foster

disruptive technology and/or other factors are at play like a worldwide decline in drug

prescriptions [2]. The modus operandi for new drug testing is, of course, the clinical trial. From

the layman’s perspective a clinical trial is simply the chance to try a new medicine in a study at

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their doctor’s office, but clinical trials have become a very complex entity that is tightly

regulated and occurs worldwide simultaneously at multiple sites. Only when the data are pooled

from multiple sites and analyzed statistically can inferences be made about efficacy, dosing, and

side effects. This article explores this complex entity in relation to the trend that many New Drug

Entity (NDE) applications to the U.S. Food and Drug Administration (FDA) have in recent years

been routinely outsourced to clinical trial sites outside the USA [3].

In a study conducted in 2007-2008 [4], it was noted that, on average, 78% of all clinical

trial subjects were enrolled from non-U.S. sites, and 54% of the clinical trial sites were outside

the USA. More recent data could not be found, but it is accepted that overseas sites are steadily

increasing. There are, of course, advantages to free trade which were discussed when this paper

was presented at the First International Research Forum at Mississippi College (April, 29, 2014).

The author is not an advocate of U.S. entrenchment, protectionism or isolationism. Nonetheless,

it goes without saying that America should be the prime place for studying those diseases that are

predominantly plaguing America, i.e., diabetes, cardiovascular disease, and obesity. Obvious

intrinsic factors (i.e., genetics) as well as extrinsic factors (i.e., lifestyle and diet) make America

unique and clinical trials should not ignore these. Moreover, America has been the historic leader

in medical research for over 100 years, so why should so many clinical trials go overseas? This

question has not played well in lay articles in 2008 in the New York Times [5] and in 2011 in

Vanity Fair magazine [6]. These lay articles made the case that as clinical trials are preferably

placed in developing countries, that the pharmaceutical companies have shifted responsibilities

to “money making” Clinical Research Organizations (CROs) and away from “pure” academia.

As one analyst wrote “Although the companies trumpet that their primary concern is the interest

and well-being of the patient, few believe this message and many discount it as cheap

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propaganda” [7]. Thus, the issue of overseas clinical trials has major public relations

implications.

“Go overseas” seems the unquestioned business model for the current clinical trials

industry. This fact is ascertainable by anyone wishing to search http://clinicaltrials.gov, a

government website for research volunteers, where one can search by sites and countries. Back

in 2008, there were approximately 6,500 non-U.S. clinical trial sites monitored by the FDA, and

60% of them were in western Europe [4]. By 2014 a new trend has emerged that clinical trial

sites are shifting to Brazil, Eastern Europe, Russia, India, and China. These “BEERIC” countries

possess big populations, good enough clinical infrastructure, and low labor costs compared to

sites in western Europe or North America. A good public relations response to this is that

overseas out-sourcing of clinical trials is necessary given the urgency for new treatments coupled

with the hope that clinical trials will move faster… and one way to move them faster is to open

the doors for testing in other countries. The FDA monitors all sites worldwide for clinical trials

according to standard Good Clinical Practices (GCPs), and for this reason many FDA offices and

inspections exist worldwide. Since the FDA maintains high standards, then allowing a worldwide

net of recruitment only leads to more rapid completion of the clinical trials, bringing new drugs

to the marketplace quicker, and ultimately promoting the public health. Whether or not this is

100% true or merely good public relations, it bears noting that around the same time that

America’s clinical trial sites became less than half of the equation (about 10 years ago) is when

Big Pharma’s pipeline started to stagnate.

At the same time, Big Pharma may not be totally at blame for seeking BEERIC countries

because there seems to have developed in recent years a widespread disinterest amongst many

US physicians about conducting clinical trials. This is borne out because the overall numbers of

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US sites for clinical trials has dropped by about 50% in the past 5 years (statistics from the

American Clinical Research Professionals: ACRP). In conversations with physicians regardless

of their ethnic background, the author has repeatedly heard that clinical trials have become too

complex, the rewards aren’t clear enough, and the regulatory paperwork is overwhelming. Thus,

there are two sides to the coin.

Some of the implications of this article go well beyond the author’s scope; writing from

the perspective of a small clinical trial site network in Mississippi trying to work through the

health disparities portion of the clinical trials industry [8, 9]. From this author’s vantage point,

the imbalance towards clinical trials overseas is worrisome.

Pros and Cons of Overseas Outsourcing of Clinical Trials

The rationale most often cited for outsourcing overseas is higher numbers of patients. A

leading consultancy firm (Value of Insight Consulting, Inc.) wrote in a 2007 online editorial that “it

would require approximately 5.8 years to fully enroll all currently open Phase-3 cancer trials if

only U.S. locations were used as compared to 1.9 years using both national and international

sites”. Although the voracity of this calculation was unclear, yet a projected 3-fold difference is

huge in business terms. And, the reader is reminded that “urgency” has special meaning in the

pharmaceutical business since to complete clinical trials promptly is to start the flow of income

sooner, prolong the patent value, and make the stock holders very happy. Not to be cynical of

business, but good science rather than urgency should be the over-riding factor in favor of

overseas outsourcing of clinical trials — and this author remains unconvinced that good science

is always over-riding. Other cited benefits like lower labor costs overseas may in fact be offset

by the expenses involved in maintaining a worldwide supply chain, dealing with multinational

regulatory agencies, currency exchanges, language barriers etc.

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The current globalization of clinical trial research also raises many important questions

about the ethics of the drug approval process. In fact, which countries ethical standards should

apply is a complex legal question [10]. Are the results accurate and valid, and can they be

extrapolated to an American setting when the drugs are marketed? It may be admissible that

“any” human research participant on a new HIV/ AIDS medicine can suffice in a study of a virus

that strikes across human boundaries , but for diseases like obesity and heart disease is it proper

that the American consumer ends up with dosing schedules and package alerts which were

ascertained mostly overseas?

There is also the issue of health disparities that is faced daily in most Mississippi clinics.

With such disease disparities persistent in America, many ask why are African Americans and/or

Hispanics not being adequately studied in clinical trials [11]? How bad the situation has gotten

was not readily available until recently; but, in 2012, the US Congress, in Section 907 of the

FDA and Innovation Act (FDASIA), directed a report be prepared on the inclusion and analysis

of demographic subgroups in clinical trials. Specifically, Congress asked the FDA to consider

four key topics: tools to ensure submission of demographic information, subset analysis,

demographic subgroup participation in clinical trials submitted to the FDA in support of product

applications, and communication of this information to health care professionals and the

American public. In compliance with that request, an FDA-wide working group evaluated a set

of 72 applications approved during 2011 for NDE products plus original biologics and Class III

devices (premarket approval)[12]. Most of the 72 applications came from Big Pharma. In regard

to racial inclusion they found that Caucasians were by far the most studied (82%), followed by

Asians (8%), followed by African Americans (6%), followed by a mixture of Hispanics and

others (4%) [12]. This report is a welcome historic step forward but it unfortunately used a “one

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race anywhere approach” rather than listing the racial demographics according to where they

were actually recruited (USA subjects or overseas subjects). More data from that report is

discussed later in this article.

African Americans, and all others, are legally guarded against coercive tactics and

systematic misinformation about clinical trials. This protection was enacted into law as fallout

from the ugly Tuskegee Syphilis Study of the 1930’s-70’s. The National Institutes of Health

(NIH) Revitalization Act of 1993 mandated there henceforth be appropriate inclusion of

minorities in all NIH-funded research. Yet, African Americans and Hispanics are still woefully at

the end of the line when it comes to the fruits that a democratic society should offer to every

citizen once clinical trial advancements are made. This is not because the new medicines are not

sold to these minorities, but because these minorities were barely recruited and studied in clinical

trials and therefore whatever unique dosing and/or side effects may be minority-specific have

gone undetected prior to marketing. Much has been made of the so-called “wariness factor” from

the Tuskegee Study as the main factor explaining low enrollment of African Americans in

clinical trials [13]. Instead of saying that African Americans are too wary to enroll in clinical

trials, this author wonders if the more major factor causing health disparity is simply where the

clinical trials are being run. If the trials are run overseas, how can African Americans be

studied? Education and trust are undeniable elements towards enrolling more minority research

participants [11], but access to the clinical trials is paramount.

The reader is further reminded that those US clinical trial sites that still actively

contribute on average 20% of the overall clinical trials data, are not homogeneously dispersed in

America. In fact, they are preponderantly clustered around the headquarters of Big Pharma and

the affiliated CROs — for the sake of simplicity I will call this the “east coast /west coast

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distribution” — though it is a gross geographic oversimplification. Whatever one calls this

uneven distribution, it amounts to a bias for recruitment that is mainly overseas, or east coast, or

west coast. The people in these places are largely Caucasians and differ in many lifestyle ways

from those in the author’s state of Mississippi.

How Did We Get Here and Who Cares?

NDE clinical trials began transitioning some 50 years ago from pharma-owned and

operated sites, to at first outsourcing within US major medical centers (circa 30 years ago), then

to outsourcing within US private practices (circa 15 years ago), and finally to the situation since

at least 2007-08 when 78% of the research subjects are recruited and studied out-of-USA [5].

These non-USA sites are often based in private hospitals and/or specialized clinical trial sites.

Furthermore, a 2010 report [4] from the U.S. Inspector General showed concern for the ability of

the FDA to adequately monitor so many overseas clinical trial sites .

Also at the top of the “Who Should Care List” is the National Institute of Minority Health

and Health Disparities (NIMHHD). They, and the NIH in general across institutes, have always

promoted clinical trials in the USA. Mississippians in recent years are particularly thankful to the

NIH for the first-ever clinical trial of heart disease for African Americans: the Jackson Heart

Study. The Jackson Heart Study has helped clarify that full minority recruitment requires

diversifying research teams, recognizing past research abuses, and increasing community trust

[14]. All the same, the NIH rarely funds NDE clinical trials, which are largely relegated to Big

Pharma. Furthermore, to my knowledge the NIH has not spoken pros and/or cons of outsourcing

clinical trials overseas whether in relation to minorities, or for that matter to all Americans.

Next, in terms of who should care, is the pharmaceutical industry itself. Although this

article has made a point that the business tendency is to choose global sites based on the need of

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expediency in clinical trials, virtually all of Big Pharma acknowledges fair minority hiring ethics

and there is no reason to single them out as anti-anyone. This author has repeatedly heard

conversations across the pharmaceutical industry that if only a plan can be presented that

incorporates business success with minority inclusion then they will be very eager to run more

clinical trials using minorities and others in the USA. The problem is that the grassroots voice

from the public has not been heard loudly enough by them.

Methods Used in this Paper

After searching Pubmed for peer-reviewed articles (all fields) according to “clinical

trials” AND “overseas” AND “sites” as key words, the author found only one article.

Substituting “outside the USA” for “overseas” still yielded a mere 42 hits in combination with

“clinical trials” as key words. Substituting “health disparities” for “outside the USA” likewise

yielded a mere 19 hits. Searching the term “National Institute of Minority Health and Health

Disparities” AND “clinical trials” yielded only 20 hits. These scientific literature searches were

done in May, 2014. Of course, other literature sources were sought for this article (i.e., FDA

published reports and documents, commissioned works from the National Institute of Minority

Health, and even brokerage firm commentaries), but the fact remains that very little scientific

literature on the effects of overseas outsourcing exists. Therefore, the author has chosen to also

write this article based on his personal data gleaned from trying to set-up a clinical trials site

network business in Mississippi which, by design, was targeting investors and pharmaceutical

sponsors with the explicit business angle that in Mississippi they could recruit many African

American subjects. Following were the main “selling” points used from 2011-2012 in making an

appeal for sites business from Big Pharma and CROs to Mississippi.

We have trained Clinical Research Associates for running the clinical trials.

Private practice doctors (n=8) available with sizable practices in varying fields.

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Mississippians make good subjects, often under-insured (making more eager

enrollees).

Excellent supply chain in Jackson, MS, and on the gulf coast (our two business

regions).

Regulatory approval quickly because we use centralized review boards.

Clinical trials sites like ours, in various places in America, will have inherent face

validity and acceptability by the ultimate consumers.

Our corporate office was housed within a minority business incubator and therefore

accessible to a large African American population.

These points are listed so that the reader may assess them in light of the business results.

The article documents how a clinical trial site business fared in Mississippi over two

years (2011-2012) with the above selling points. The business used the Embedded Partnership

Model [9]. The model was designed to bring rewards as well as research rigor to private

practices in Mississippi community settings, train the physicians (of any race or ethnicity) in

clinical trials, and let them become Principal Investigators (PIs) in full partnership with the

author’s company, which by the time any contract was awarded acts as a fee-for-service

business.

This report can be faulted due its subjectivity. The results may have been better if

someone else had run the business and/or had more financial backing. Such subjectivity aside,

this n=1 experience in the clinical trials sites market, which after two years failed due to too little

response, is offered as a call for discussion how to cultivate (once again) more U.S. clinical trial

sites in diverse places like Mississippi.

Results of Start-up Company: First Clinical Trials Sites Network Business in Mississippi

The physician’s component of this clinical trial sites business is delineated in Table 1.

Only physicians in private practices (individually or as small groups) were approached and they

fell into two groups: either infrequent (at best) regarding prior running clinical trials themselves,

or they had previous experience at a different site or setting and wished to combine forces with

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my company to get going again. Large medical groups were not approached to partner with

because they were found unlikely to work with a start-up company. Moreover, any area

physicians already up-and-running as clinical trial sites were deemed unlikely to need to partner

with my company, so they were also not approached. When asked to partner in the clinical trials,

it was explained that Dr. Piletz would supervise the day-to-day logistical, regulatory, and

science/data matters, while they would become the Principal Investigators of their site, and

roughly 50% of the profits from the contracts would be portioned to them upon invoicing the

hoped-for pharmaceutical sponsor of each study [9].

As can be seen in Table 1, 33 doctors were offered this partnership proposal to join the

network [9]. Efforts were especially made to identify and recruit African American doctors. Of

the 33 approached, 12 signed-on, but after 2 years only 8 remained active. Once onboard, efforts

were also made to upgrade the infrastructure to make each site ready for clinical trials. There was

an online training course developed by Dr. Piletz so that each doctor could demonstrate

competency with the FDA as a PI, described at harborway.trainingcampus.net. Seven of the eight

doctors accomplished this training in good standing. One didn’t try it. Thus, it was found that 7

of 33 doctors approached in Mississippi private practices were willing to partner, train, and work

in partnership as a clinical trial network business. By race, this final group of PI’s was composed

of 4 Caucasians, 1 African American, 1 Chinese American, and 1 Indian American.

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• Recruiting staff - those approached to join team as either CRC or CRA: 6

• Staff who joined the team and took

online training course: 5

• Staff who joined but quit: 2

• Trained staff currently on the team: 4

Building the Network Staff:Metrics Over Two Years

Building the Site Network Doctors:Metrics Over Two Years

• MS doctors approached to join network: 33

• MS doctors who joined the network 12

• MS doctors who joined but dropped out: 4

• MS doctors currently in the network: 8

• Network doctors asked to take online

training course: 10

• Network doctors who actually took our

online training course 7

Table 1.

The staffing component of this clinical trial sites business is delineated in Table 2. Over

two years, 6 individuals with clinical backgrounds, i.e. nurses, were approached to join the staff

and be trained as either Clinical Research Coordinators (CRCs) or Clinical Research Associates

(CRAs). Five of them became part-time employees. They received hands-on training from Dr.

Piletz and also took an online training course (harborway.trainingcampus.net). Some of them

already had clinical trials experience. During the years 2011-2012, two of them quit, leaving 4

part-time employees by the end of 2012. These staff employees were fully available to work with

any of the 8 doctors in the network once a clinical trial was contracted.

Table 2.

Having created a viable business with doctors, CRCs and CRAs (Tables 1 and 2) - not to

mention the author who is fully trained and a former Principle Investigator – the company was

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constantly applying for clinical trial contracts during 2011-2012. Not only did the company

apply by completing the forms, but Dr. Piletz regularly attended all of the major meetings in the

field. In fact, part of this paper was presented by him at the 2013 International ACRP meeting.

Thus, every effort was made to attract business. The clinical trials applied for were all ultimately

from pharmaceutical companies and within the expertise range of our doctors. As shown in

Table 3, we completed the registration forms for our doctor sites with 49 different potential

sponsors for particular studies that we hoped were open (mostly CROs). We also followed-up

with telephone calls. From these applications, 7 sponsors sent the actual protocols for us to

review and bid on. On 6 occasions we also received site visitors from the sponsors to consider

our sites. Of these site interviews, we were successful only twice. The main reason given for

only landing 2 of the trials represented by 6 site visits was that our site investigators weren’t

experienced enough. Rarely, if ever, were we faulted for not having a big enough patient pool to

recruit from. Then, during the 2011-2012 period we successfully completed one of the two

clinical trials we got. The allotted quota of patients on that trial was met and the data was

delivered in timely fashion and fully accepted based on a post-study audit. Incidentally, our

second clinical trial was awarded to the same doctor for a similar study so it was clear that past

experience is crucial. However, by the end of 2012 when we’d received approval of that second

clinical trial, our central office moved and therefore we decided to sublet the project. The bottom

line is that despite many intense efforts, we were only able to obtain 2 clinical trials out of 49

that we applied for. An additional point is that these two studies were new pain management

medication studies and because of the sensitive nature or opioid diversion, all the chosen trial

sites were in America. In the final analysis, therefore, it seemed we were 0 for 40 clinical trials

that would have been open overseas.

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• Sponsors sent applications to & registered

online with for particular studies: 49

• Received 2nd-step protocols for

bidding on trials 7

• Opportunities when site visitors came: 6

• Clinical trials awarded & started: 2

• Clinical trials completed 1

Success with Pharma Sponsors: Metrics Over Two Years

Table 3.

Discussion

This paper makes a case that overseas outsourcing of clinical trials may aggravate the

fight against health disparities in the USA. The case points to more research subjects being

recruited overseas these days, and consequently there is less access for African Americans and

Hispanics into clinical trials and therefore these groups of people go largely untested before new

drugs come to market. In trying to find actual evidence for this case, the first main finding of this

paper is that nearly no scientific literature exists on the subject. Except for a few lay articles [5,

6, 15], few in the scientific community seem to be studying the effects of overseas outsourcing.

This came as a big surprise to the author.

Even more surprising was that it took a 2012 Act of Congress for a report to be published on

the racial demographics of current clinical trials [12]. What does the report show? Firstly, the

overall finding of n=72 diverse studies was that Caucasians are by far the most studied (82%),

followed by Asians (8%), followed by African Americans (6%), followed by a mixture of Hispanics

and others (4%) [12]. Unfortunately, the same holds true when looking specifically at Type II

Diabetes studies. Diabetes is 60% more common in African Americans than in white Americans.

African Americans are also up to 2.5 times more likely to suffer a limb amputation and up to 5.6

times more likely to suffer kidney disease than other people with diabetes. Yet, the FDA lists

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Caucasians are by far the most studied (67%), followed by Asians (31%), followed by African

Americans (2%), followed by a mixture of Hispanics and others (0%) in T2DM studies [12].

Many are wondering how such disparities can still exist in clinical trials despite the NIH

Revitalization Act of 1993 which mandated appropriate inclusion of minorities in all NIH-funded

research. The reason appears to be that pharmaceutical companies are exempt from NIH rules

because they do not receive NIH funding, and apparently the FDA does not feel justified to apply

the NIH Revitalization Act of 1993 to Big Pharma. Yet, what benefit has Big Pharma gotten

since the days when US sites started to provide less than 50% of the mix of research subjects?

The author of this paper suggests they have created a public relations problem and their new drug

pipelines remain stagnant.

Since no good scientific literature can be found on the effects of outsourcing clinical

trials, this paper also presents real-life data obtained by the author from his two year clinical

trials business experience. The author’s data in Tables 1-3 represents metrics obtained from

2011-12 when he was full-time dedicated to a start-up clinical trials site business model in

Mississippi [9]. This business targeted Big Pharma and CROs by asking them to consider the

percentage of African Americans that could be recruited in Mississippi. Because this was a start-

up business and based solely in private practices, it may have seemed not as competitive as well-

established sites for gaining this type of business. Nonetheless, the private practices in the

company were well trained by an experience former PI (Dr. Piletz). Given those major disparities

mentioned in the preceding paragraph the author had hoped some traction would’ve existed for

Mississippi. The results in Table 3 make it clear that obtaining contracts for clinical trials in

Mississippi private practices was not a success.

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The most common response given for rejections from the trial sponsors was that our

investigators were not adequately experienced, which is taken at face value. Nonetheless, the

owner of this business has managed clinical trial sites prior in Chicago and had spent 9 months

on a clinical trial site in Beijing, China, and therefore is persuaded that the same pharmaceutical

sponsors who’re so eagerly enlisting sites in BEERIC countries these day do not see many

better-trained or more experienced sites there than what was put together in Mississippi. Hence,

the data in Table 3 suggest that the current value of American minorities in clinical trials might

not be of much consideration when selecting sites by most pharmaceutical companies and/or

CROs. What seems to matter for US sites to be competitive is previous experience - and then

there are the overseas sites being in majority.

What can be done? As this article enters the scientific literature base, it is hoped that it

will stimulate more thought and discussion about the current state of low recruitment of research

subjects in general — and minorities in particular — within the USA. Most importantly, it seems

that a grass roots voice needs to emerge for the FDA, Big Pharma, and the CROs to take notice.

Acknowledgements

The author thanks his site PIs, especially Dr. Brian Tsang, and many research associates for their

insights and help in developing the Embedded Partnership Site business model. The author has

no financial interests that would present a conflict of interest.

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