Medical Research & Drug Prices: One Patient’s Perspective

March 26, 2011

a patient perspective on medical research

Medical Research:
A Patient Perspective

Do patients always benefit from clinical trials and medical research? Are patients consumers? There is an assumption that medical research automatically correlates into improved outcomes for patients, particularly those with chronic medical conditions, such as diabetes, or with life-threatening conditions, such as many forms of cancer. However, their are different viewpoints. After the recent anger over drug price hikes for pregnancy and MS drugs GxP Perspectives requested a Guest Commentary by Marc Stecker, who has multiple sclerosis, and is the author of the blog, Wheelchair Kamikaze: “The Rants, Ruminations, and Reflections of a Mad MS Patient.” He is also an outstanding photographer and his photo, “rail-shadow” is featured above left. Because Marc’s commentary is different than most on this blog I am going to start with his concluding comment. I think it will help put things into perspective:

“I’ll let my final words on the subject be these: As responsible members of a just and honorable society, please, view me first as a patient, not as a consumer. Human suffering should never be treated as a commodity, regardless of the considerable economic incentives to do so.”

There will be differing reactions to the viewpoints expressed in Marc’s Guest Commentary. Please feel free to comment with your own views.

Guest Commentary

A Patient Perspective on the Mechanics of Medical Research
by Marc Stecker

Although there have been some incredible advances made in our efforts to heal sick humans over the last 50 years, there are still vast swathes of patient populations whose illnesses remain poorly understood, insufficiently and ineffectively treated, and ultimately incurable. Problematically, many of these patient populations generate billions and billions of dollars for the modern medical hierarchy, a situation that sets up a paradox within our profit driven medical establishment. Cure these patients, and vast sums of money and an elaborate infrastructure would simply evaporate; keep them perpetually reliant on hyper expensive medicines and medical procedures, and reap the fruits of an unending money machine.

Before I am accused of being a conspiracy nut, let me state outright that I do not believe that there is a cabal of evil, mustache twisting, demonic connivers assembled around a huge flaming conference table, snacking on deep-fried baby’s arms while plotting to keep cures and remedies hidden and out of reach from the desperately ill. If this were the case, the solution would be fairly straightforward; simply “out” the conspirators, and the walls come tumbling down. Rather, the problem has become incorporated into the system itself, insidious and inherent, the logical outcome of the evolution of a medical industrial establishment that has come to view sick people as consumers and horrendous illnesses as opportunities for tremendous financial gain. This system does not require people with malicious intent to keep it functioning; it only needs decent people doing their appointed jobs to the best of their abilities to keep the gears turning.

The job of a publicly traded pharmaceutical company CEO is to constantly drive up the price of his company’s stock, not to facilitate the creation of drugs that would be of the most benefit to the patients taking them. This isn’t a question of morality, but of economics. The drug companies, and those who manage them, are merely doing what every other business endeavors to do in our free-market capitalist system, constantly increase profit. I’m all for free-market capitalism; in recorded history there has been no better economic driver and creator of wealth. Unfortunately, when applied to healthcare, in many cases good economics has led to very bad medicine.

medical research patient perspectiveGiven that the mission of pharmaceutical companies is to generate the most bang for their research bucks, their research dollars are directed to projects that have the best possibility of leading to substantial profit. This, in turn, influences the behavior of even the most well-meaning medical researchers, who, just like everybody else, need to feed their families, pay their bills, and naturally seek to advance their careers. Thus, they are drawn to investigations that will most likely win hotly contested research dollars. That funding, the vast majority of which comes from the big pharmaceutical companies, goes almost exclusively into researching novel compounds that can be patented and remain the sole property of the company that discovers them for many profitable years.

I’ll let my final words on the subject be these: As responsible members of a just and honorable society, please, view me first as a patient, not as a consumer. Human suffering should never be treated as a commodity, regardless of the considerable economic incentives to do so.

=======

Please see Marc’s Blog, Wheelchair Kamikaze where you can read more of his viewpoints and see his photographs .and videos. Here is one of his videos which is quite funny.

The Wheelchair Kamikaze in Central Park
======

Read the blog FDA Matters, on Drug Pricing

Time Magazine on Drug Price Anger

31 March 2011: MedPage Today: FDA allows compounding of pre-labor drug

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

=====

GxP Perspectives is now on twitter: @GxPPerspectives

Follow GxPPerspectives on Twitter


FDA Issues New Guidance for Sponsor & CRO Inspections

March 19, 2011

FDA guidance sponsor CRO inspections

FDA Issues Updated Guidance on Sponsor & CRO Inspections

FDA is increasing their emphasis on Sponosr and CRO inspections with the release of an updated version of the Compliance Program Guidance Manual, CP 7348.810, Sponsors, Contract Research Organizations, and Monitors (CPGM). This FDA guidance document gives instructions to FDA personnel on how to conduct an inspection of a sponsor or CRO involved in FDA regulated research.

It significantly modernizes the previous CPGM, released over 10 years ago, introducing new sections and deleting sections that were obsolete or irrelevant.

There are new sections on the Registration of Studies on ClinicalTrials.gov; Review of Site Records; Financial Disclosure; Electronic Records and Electronic Signatures; Emergency Research; International Data; and GLP Studies. Other sections, such as Medical Devices, are substantially updated and clearer. The new CPGM should professionalize FDA’s approach to sponsor and CRO inspections and ensure closer review of a sponsor’s regulatory responsibilities. It is long overdue. I have done a brief analysis of Section III, Inspectional, of the new CPGM. There are also some helpful links to documents in Section VI, References and Contacts including several documents that I had never heard of before.

FDA inspection guidance on sponsors and CROs

Sponsor and CRO Inspections Usually Will be Scheduled

The first significant change is right at the beginning of Section III, Inspections, “under this program will be pre-announced unless otherwise instructed in the inspection assignment.” This formalizes a policy that began a few years ago under the Medical Devices Initiative. In addition, the new CPGM makes a point of emphasizing a statement routinely included in FDA inspection documents: Approaches that differ from those described in FDA’s Guidance documents should not be listed on the (Form FDA) 483 (Inspectional Observations) unless they constitute deviations from the regulations.” There are also instructions that the new CPGM “provides only the minimum scope of the inspection” for the field investigator to “expand the inspection as the circumstances warrant.” There are also specific instructions on how to document a violation:

“Any deviations from regulations should be thoroughly documented. For example, if the sponsor failed to review monitoring reports in a timely fashion and/or failed to bring non- compliant clinical investigators into compliance, monitoring reports, report review dates, and evidence of clinical investigator continued non-compliance should be documented and copied.” (original emphasis)

There are specific instructions that stem from FDA’s increased vigilance regarding falsification of data:

FDA sponsor inspection

Increased Emphasis on Falsification of Data

“Discuss potential violations involving fraud subject to Title 18 of the United States Code (18 U.S.C.) with your supervisor, District Compliance Officer, and assigning Center contact for appropriate referral to the Office of Criminal Investigations (OCI).” Reader’s should note that Title 18 violations are the ones that can put you into prison. Here are the new sections of the CPGM:

D. REGISTRATION OF STUDIES ON CLINICALTRIALS.GOV

“ClinicalTrials.gov is a website maintained by the National Library of Medicine (NLM). Its establishment was mandated by the 1997 FDA Modernization Act (FDAMA) to provide a public resource for information on studies of drugs, including biological drug products. The FDA Amendments Act of 2007 (FDAAA) mandated expansion of this data bank and included enforcement provisions to help ensure compliance.” There are specific guidance instructions in this section including a discussion of the Form FDA 3674, which we all will be paying closer attention to. Among the additional instructions to FDA field investigators are:

“6. Determine whether primary and secondary outcomes measures are listed on ClinicalTrials.govfor the study/studies. Determine if the outcome measures, if any, listed on ClinicalTrials.gov are generally consistent with the primary and secondary outcomes in the sponsor’s study protocol(s).

7. When examining informed consent documents related to an applicable clinical trial registered on ClinicalTrials.gov, determine if the appropriate required statement referencing ClinicalTrials.gov is included6. 21 CFR 50.25(c). The statement is:

‘’A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.’’’

For the section on Monitoring Procedures and Activities there is one significant change in recognition of the changes in the conduct of clinical trials: “With the prevalence of multisite clinical trials, traditional monitoring techniques – early and frequent on-site visits at all clinical sites – have become resource intensive. Regulations do not prescribe a specific monitoring technique, simply stating that sponsors are required to select monitors qualified by training and experience to monitor the investigational study (21 CFR 312.53(d), 511.1(b)(8)(ii), and 812.43(d)).”

FDA sponsor CRO inspections guidance

Monitoring of Clinical Trials is Evolving

In part, this statement recognizes that 100% source/CRF verification might not be practical or necessary, that sponsors may need to adapt new techniques, sometimes described as “Compliance Monitoring,” where monitoring records and reports are reviewed to determine outlier data. This could include no adverse events reported at a specific site. The CPGM goes on to state: “Determine if all CRFs are verified during monitoring visits. If a representative sample was selected, determine how the size and composition of the sample were selected.”

Financial Disclosure is discussed for the first time by FDA in a CPGM. Financial disclosure violations are very rarely cited by FDA during sponsor/CRO inspections. This may change with these instructions:

“1. Determine if the sponsor obtained financial disclosure information from each investigatorbefore his/her participation in the clinical trial, as required by 21 CFR Part 54 and 21 CFR 312.53(c)(4) and 812.2(b)(5) and 812.43(c)(5).

2. Determine if the sponsor received prompt updates regarding relevant changes in financialdisclosure information from investigators during the study and for one year after study completion.

3. Determine if the sponsor reported to FDA (on Form FDA 3454 and 3455, respectively), allpertinent investigator disclosures and certifications of financial information as required by 21 CFR 54.6.

4. Determine if the sponsor retained the documentation to support the certifications anddisclosures of investigators’ financial information that was reported to FDA.”

FDA inspection of sponsor

Updated Section on
Part 11

There is an updated section on Electronic Records and Electronic Signatures. The FDA guidance document, “Guidance for Industry Part 11, Electronic Records; Electronic Signatures – Scope and Application” (Part 11 Guidance) is discussed at length confirming that this document currently represents FDA’s enforcement policy regarding Part 11.

The CPGM emphasizes issues including the Scope of Electronic Records & Signatures; Procedures; Data Collection; & Security.

Finally there are new sections on Emergency Research; International Data; & Nonclinical Laboratories reflecting new regulations, guidance documents, or inspection policies. It is important to note that although FDA will not inspect GLP studies at every sponsor/CRO inspection, the possibility exists. The new CPGM gives the field investigator specific instructions on what to look for in non-clinical studies. (UPDATE: Read the recent Sponsor Warning Letter on Preclinical Studies on the link below.)

The new CPGM will significantly change how Sponsor/Contract Research Organizations, and Monitor inspections are conducted. It confirms a shift to review of sponsor responsibilities by FDA’s Bioresearch Monitoring program managers. It is a very important document for sponsors and CROs to review.

Read the New CPGM

Guidance for Industry on Financial Disclosure

Guidance on Certifications Required By FDAAA (including clinicaltrials.gov)

Compliance Policy Guide on Fraud and Untrue Statements…

Part 11: Scope & Application Guidance

Sponsor Warning Letter on Preclinical Studies from CDRH

====

You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).

Please take a short 3-question survey to help GxP Perspectives improve! Survey begins 22 SEP 2011

====

On the Blogroll:

Marc Stecker’s Photos

=====

On the Blogroll: FDA Matters once again discusses the importance of FDA’s contributions to public health. Please read Steven Grossman’s post on Change Takes Time.

=====
Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

=====

GxP Perspectives is now on twitter: @GxPPerspectives

Follow GxPPerspectives on Twitter


FDA Inspections: What NOT To Say & How Not To Say It

March 13, 2011

FDA inspections

"It's Not My Job"

FDA Inspections are Always stressful. How should you answer the FDA Investigator’s questions? What should you say or, more importantly, what should you NOT say? Two common answers are to tell the truth and to only answer the question asked. Both are good points. The FDA investigator is conducting a public health inspection so you should want to tell the truth. It also happens to be against the law to lie to a federal official so there are both positive and negative motivations to answer a question truthfully. It is also a good idea to give a brief, factual, and truthful answer to the question you are asked, not a question you think might be asked. And remember to use a complete sentence. Receiving a barrage of monosyllables in an interview is only going to irritate the FDA investigator. The one answer I recommend to never give to an FDA investigator is, “It’s not my job.”

What? Most people who answer, “it’s not my job” are telling the truth! Not only that, it is not a good idea to answer for someone else who actually has that responsibility. However, you have to remember that an FDA investigator has heard that response one hundred times before. People frequently give evasive answers and avoid responsibility when being interviewed by the FDA. It gets very old, very fast.

FDA inspection

"I Know Who Has That Responsibility"

A better approach is to say, “That isn’t my job but I know whose responsibility it is and let me see if she is available.” During an FDA inspection it is important to build trust. If an FDA inspector asks a reasonable question, let’s say, “How do you ship investigational product to clinical sites?” It is in your interest to see that the right person answers the question and that you find the right person in a timely manner.

FDA has begun a program to increase the types of GCP inspections it conducts. There will be more inspections of CROs and clinical trial vendors such as clinical laboratories. In fact, they have already started. That means that many more people will need training on how to participate in an FDA inspection. GxP Perspectives will be having some Guest Commentaries on the subject and try to provide some practical solutions.

FDA Inspevtions

Frontloading Quality:
The Key to Success

The first step in successfully hosting an FDA inspection is to have a quality system in place that monitors the data or product lifecycle. You don’t want to start your quality process after you lock your database! Then, when FDA does show up, you want to give a positive impression. You want to build trust with FDA. Think back to the last time you phoned your utility company or complained about a pothole on your street. When you finally got a live person and they told you, “that’s not my job,” how did you feel? That isn’t how you want FDA to feel either.

============
A new service: Please check out the Services page at the top of the Blog to learn more about GxP Services.
============

============
Take the GxP Survey! Only Ten Questions!
============

Here are some helpful articles and resources on FDA inspections:

Applied Clinical Trials on Mock FDA Inspections.

Ten Steps for Improving GCP Inspections by Vernette Molloy and my late colleague, Sandy Mackintosh, also in Applied Clinical Trials

FDA Inspection Guides: How the FDA conducts inspections

BioJobBlog: What’s Up With FDA Inspections Anyway?

#######

SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.

##########
A new feature from FDAzilla on FDA 483s

Read the Press Release on 483s

On the Blogroll: GxP Perspectives made the list for Best 40 Blogs (and tweets) on the FDA. This comes from FDAZilla. I think it is a pretty good list.

##########

Follow GxPPerspectives on Twitter

Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.

+++++++++

On The Blogroll: Audrey’s Network– a great way to keep up with news from the San Francisco Bay Area Life Sciences Community

Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group


GCP Protocol Deviations & Violations: Determining the Root Cause

March 6, 2011

protocol violations and deviations GCP

GCP Protocol Violations: Determing the Root Cause

The top violation cited during FDA inspections of clinical sites has consistently been the failure to follow the investigational plan- Protocol Deviations & Violations. Coupled with recordkeeping violations the failure to follow the protocol has been the mainstay of the Form FDA 483, Inspectional Observations, issued by FDA field investigators to clinical sites for decades. However, FDA has recently been pointing out that the root cause can just as easily be poorly designed protocols as noncompliance by a clinical investigator. In the previous post on GCP CAPA plans I note that at least two root causes that should always be investigated. This is particularly true when you find systematic protocol violations. Two areas that should always be reviewed are:

Protocol Design: Frequently you will find a Note to File in a clinical site’s regulatory binder saying that the study coordinator had been “retrained” in the importance of subject compliance. However, if subjects are routinely missing visits or protocol-required procedures you need to take a look at how well designed the protocol is. Were clinical sites consulted when the protocol was written? Is the visit schedule practical? Are the tests easily performed or do they require special efforts by research staff at a busy medical practice? And just how many protocol amendments do you have anyway? It is the clinical site that will receive an FDA 483 but the root cause very well might be found at the sponsor.

GCP Violations and protocol deviations

Protocol Violations are the Top GCP Violation at Clinical Sites

Protocol Adherence: Sometimes the clinical site is the cause of the deviation. There is a significant difference between the practice of medicine and the conduct of a clinical trial. I can’t count the times that I have been told, condescendingly, that “We’ve been doing this type of medical procedure for quite some time.” That’s all well and good but have you been reading the protocol for quite some time? A clinical trial is an experiment, and frequently requires activities that are not the usual practice of medicine. You may need to order a second blood test, or change the dose of the investigational product.

In cases like this a follow-up letter from the monitor to the clinical site might not be enough. If the root cause is the failure to understand the responsibilities of a clinical investigator then the issue may need to be escalated to someone with the letters “MD” after their name. Sometimes you need a physician to explain the protocol to another physician. Seldom does the “re-education” of support staff work as an effective corrective action.

Determining the root cause of systemic protocol deviations and violations isn’t always easy. However, if you don’t follow the investigational plan you can jeopardize your application. And remember, always investigate at least two possible causes of protocol violations.

==============

In a recent FDA Warning Letter protocol violations are discussed at length.
====

You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).
This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)

====
On the Blogroll: Cancer Sucks

Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.
======
Please join GxP Perspectives on LinkedIn at:

GxP Perspectives LinkedIn Group

#######

SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.

I am in the process of writing an analysis of this updated compliance program. Please let me know if you have questions or suggestions for points to consider. Thanks!

##########


%d bloggers like this: