Health Care Globalization and Patients Without Borders

The term 'globalization' is nothing new. According to Wikipedia, "globalization describes an ongoing process by which regional economies, societies, and cultures have become integrated through a globe-spanning network of communication and trade. The term is sometimes used to refer specifically to economic globalization: the integration of national economies into the international economy through trade, foreign direct investment, capital flows, migration, and the spread of technology." Globalization certainly has its benefits, but it has its victims too, and the results can be deadly. As the global economy knits countries closer together, it becomes easier for diseases to spread through states, over borders and across oceans.

Globalization has impact on the medicines we take (many of them are manufactured outside of a specific country) and the conduct of the clinical trials (the clinical trial data are cross borders from multiple nations). Last year, when I attended the FDA/Industry Statistical Workshop, the theme of the workshop is 'global harmonization' - another way to say 'globalization'.

Recently I attended a conference in Duke, the focus again was 'globalization' with emphasis on Asia. One session discussed the tourism medicine and 'patients without borders'. It will be trend that with globalization, patients can cross border to choose the health care that will better service them (with cost and quality of care in mind). One day, we could share the health care resources much like the sharing of the technologies.

I also understand that the sharing of the health care resource will not be an easy task. Several days ago, one of my American colleagues asked me if it is possible for foreigners to have renal (kidney) transplantation in China (for obvious reason of the shortage in kidney donors). When I posted the question to my alumni email list, I immediately got some response such as the one below "I believe that all Chinese with renal failure have the absolute right for having kidney transplant in China. As a Chinese, I strongly against any give away of basic human right..."  I sort of agree with this. The world is not ready to share the health care resource (at least the organs for transplant).

Within the country, there may or may not be any policy or procedure to ensure the fairness between the rich and the poor, not to mention the fairness across countries.

China actually has its policies on organ transplantation including renal
(kidney) transplantation.The policies basically prohibit the tourism medical treatment in China for organ transplantation.

卫生部办公厅关于境外人员申请人体器官移植有关问题的通知 (General Office of the Ministry of Health personnel for human organ transplants outside the Issues)

人体器官移植条例 (Human Organ Transplant Ordinance)

Dealer's choice

According to dictionary.com, the term "dealer's choice" is defined as "

a card game, as poker, in which the dealer decides what particular game is to be played, often depending on the number of players, and designates any special variations or unusual rules, including setting the stakes."

In contrary to the randomized clinical trial, an approach called "dealer's choice" has now been used in clinical trials  or in clinical setting (more often in oncology clinical trials) where the treating physician decides which treatment regimen will be given to the patients/subjects. Typically, this happens when there are several treatment regimens, but there is no sufficient information to decide one is better than others. 

While this is ok for treating the patients in clinical setting, it is not ideal when this approach is used in clinical trial. # of subjects who receive on specific treatment regimen will depend on the dealer's choice and may be imbalanced in terms of the sample size and the subject characteristics across different regimens. At the end of the study, if there is any difference among treatment regimens, there may be due to the 'unknown' confounding factor rather than the treatment itself. 

Here are some of the examples using "dealer's approach": 

An intergroup rectal cancer trial supported by NCI employed the dealer's choice approach in which treatment would be chosen by the physician and patient together.

Interventional Management of Stroke (IMS) III Trial (IMSIII) did not explicitly use the term "dealer's approach". However, in the investigational treatment arm, after initial tPA treatment fails, the doctor will choose--based on the location and extent of the blood clot--one of 4 possible IA treatments given directly in the brain artery that will be most effective in reopening the blocked artery. There is no randomization. It is dealer's choice in choosing one of the four treatment options. 

 

There may be legitimate reason in using "dealer's choice" approach, it certainly compromise the quality of the trial and make the interpretation of the results more difficult.

Ghost writer, ghost surgeon,...

"Ghost writing" practice has been criticized recently due to the reveal of details targeting several big pharmaceutical companies. With medical ghostwriting, pharmaceutical companies pay both professional writers to produce papers and then pay other scientists or physicans to attach their names to these papers before they are published in a medical or scientific journals."Ghost writer" may never be acknowledged in the publication. Wyeth was actually sued over the ghost writing practice (see reports from NPR and New York Times). Other companies had similar practices: for example, Merck's case and GSK. New York Times recently reported that Drug Maker Wrote Entire Book Under 2 Doctors’ Names.

“To ghostwrite an entire textbook is a new level of chutzpah,” said Dr. David A. Kessler, former commissioner of the Food and Drug Administration, after reviewing the documents. “I’ve never heard of that before. It takes your breath away.”

Actually, "ghost writing" practice has been out there for many years and it is not just in pharmaceutical industry. Celebrities, executives, and political leaders often hire ghostwriters to draft or edit autobiographies, magazine articles, or other written material.No wonder they can publish nice books and articles.

Perhaps, there is nothing wrong in terms of the business model. Medical writer and freelance writer get pays for their services and whether or not being acknowledged is not important to them.

Recently, I heard a new term "ghost surgery": a practice of performing surgery on another phycian's patient by arrangement with the physician but unknown to the patient.A famous surgeon could make an arrangement to have a substitute (perhaps a resident) to perform the surgery without patient's knowledge (patient could be unconscious). What can you do about this practice? can you sue? Not necessarily. 

Ghost writer and ghost surgeon are certainly not all 'ghost' out there. There are far more 'ghost' in our daily life and in business practice.

Non-inferiority clinical trials - now comes FDA's draft guidance

In contrary to adaptive design clinical trials, non-inferiority (NI) design has been there for many years (15-20 years) and many studies have been conducted using non-inferiority design. Many products have been approved by regulatory agencies with based on the pivotal studies in non-inferiority design.

Even though there have been tons of presentations, workshops, and text books about the non-inferiority clinical trials, there is no formal guidance from FDA regarding the inferiority clinical trials (until this week).

This week, FDA issues its draft guidance for industry: non-inferiority clinical trials. The guidance gives advice on when NI studies can be interpretable, on how to choose the NI margin, and how to analyze the results.

NI is considered a special case of equivalence trial with NI comparing to only lower or upper bound of the confidence interval (but not both). While there are many other issues to be considered when design a NI trial, the selection of the NI margin continue to be a key issue in NI design. For a confirmatory trial for licensure, NI margin must be discussed with regulatory agencies and must be agreed by them. Generally, the wider the margin, the easier the NI trial to be successful. the smaller the margin, the larger the sample size. 

It is good to see that the guidance includes a question/answer on "in the situation where a placebo-controlled trial would be considered unethical, but a non-inferiority study cannot be performed, what are the options?" Unfortunately, the answer to this question is somehow not clear.

Further readings:

• Slide presentation by Bob Temple "FDA experience and perspective on non-inferiority trials"
• EMEA "Guideline on the choice of the non-inferiority margin"
• EMEA "Points to consider on switching between superiority and non-inferiority"
• Slide presentation by Bob Temple "Active control non-inferiority studies theory, assay sensitivity, and choice of margin"
• Mary Foulkes "non-inferiority specification of delta"
• Lin et al "Statistical issues in specification of delta"