Category Archives: Ethics

08Feb/12

The Most Important Proposed FDA Rule No One Is Talking About

By James McCormack PhD

On February 19, 2010, FDA published a proposed rule [75 FR 7412] that, when finalized, will have a profound effect on sponsors and the relationship between sponsors and persons they hire to plan, design, perform, review, or report biomedical research.  The proposed rule titled, “Reporting Information Regarding Falsification of Data”, will require sponsors to report to FDA, information indicating that any person has, or may have, engaged in the falsification of data in the course of performing their duties. 

Why does FDA believe this regulation is necessary?  The answer to that question can be principally found in the disqualification of a clinical investigator, Dr. Robert A. Fiddes, in June 1999 (See FDA’s Debarment Order, Clinical Investigator Disqualification List, and the Notice of Opportunity for Hearing). Among the many acts of falsification, he created false case reports for subjects that were never enrolled or did not exist, forged signatures on informed consent forms for the respective subjects, falsified records of medical procedures that were never performed, substituted test results from subjects who met the study’s inclusion criteria and improperly substituted for other subjects who did not meet the inclusion criteria, and paid Individuals, who were not study subjects, to give specimens in place of false study subjects.  Although Dr. Fiddes conducted studies for 47 sponsors affecting over 90 applications his actions were not reported to FDA.  Out of concern for the integrity of the preclearance review process and the rights and welfare of research subjects, FDA investigated why such widespread falsification could have gone unreported.  The agency determined that there was some ambiguity in the regulatory requirements regarding what information and when sponsors were to report information on possible incidences of falsification.  Therefore, the agency has proposed this rule to clarify a sponsor’s reporting requirements for studies conducted by, or on their behalf, or a study on which a sponsor relies to support a product approval.

            What research is covered by the proposed rule?  The reporting requirements will apply to information related to studies including, clinical investigations, nonclinical laboratory studies, and clinical studies in animals.

            What products are covered?  All FDA regulated products; food, drugs (human and veterinary), biologics, and medical devices.

            What do sponsors have to report?  The proposed rule does not require sponsors to make a definitive determination of falsification or establish the intent of the person who may have committed data falsification.  A sponsor is responsible for submitting information that they are aware of that a person has, or may have, falsified data.  The agency intentionally did not propose a specific threshold of information or the form, quantity, or reliability of the evidence that a person may have falsified data.  It seems apparent that the agency intends the reporting requirement to be an intelligence gathering activity that will be subject to further investigation and evaluation before serving as the basis of administrative or enforcement actions.         

When do sponsors have to report?  Under the proposed rule sponsors are required to report information they have regarding falsification, or possible falsification, to the appropriate FDA Center, no later than 45 calendar days after becoming aware of the information.

How do sponsors distinguish falsification from unintentional errors?  This is perhaps the most intriguing question raised by the proposed rule.  The agency addressed the distinction by defining “falsification” as creating, altering, recording, or omitting data in such a way that the data do not represent what actually occurred.  The proposed rule provides examples of unintentional errors, e.g., typographical errors and transposed numbers or characters, and states that such events should not be reported under the proposed rule. 

The public comment period ended in May 2010.  It is likely that the rule be finalized soon and the biomedical research environment will change accordingly.  Sponsors will need to develop robust controls to assure that possible incidences of falsification are detected, evaluated, and reported and persons performing services for sponsors should consider implementing their own controls as sponsor scrutiny will certainly increase.    

Dr. James McCormack presently serves as the Vice President of Life Sciences Compliance, at IBM.  He previously served as the Corporate Vice President of Regulatory Affairs and Compliance at Charles River Laboratories following an 18-year career in FDA as a preclearance review scientist and as FDA’s Bioresearch Monitoring Program Coordinator. 

The views expressed in this article are those of the author and do not necessarily represent those of his employer, Life-Science Panorama, its editor or Axendia, Inc.

20Oct/08

Presidential Candidates Agree on Drug Re-Importation – That is Not Fair

By Daniel R. Matlis

Although Senators McCain and Obama (listed in alphabetical order) are looking to address many of the same problems, they have very different approaches.

The Presidential candidates don’t agree on many things, from the economy to energy, healthcare to taxes, even Joe the Plumber.

One thing they both agree on: Drug Re-importation.

John McCain will look to bring greater competition to our drug markets through safe re-importation of drugs and faster introduction of generic drugs.

Barack Obama and Joe Biden will allow Americans to buy their medicines from other developed countries if the drugs are safe and prices are lower outside the U.S.

I thought it would be worth discussing some facts about drug re-importation:

FACT: You can buy many pharmaceutical drugs abroad for a lower price.
FACT: Some of these drugs are made by the same company at same plant, to the same standards as those sold in the US.

So why is a 30 day supply of 20mg Lipitor available for $60.78 on CanadaDrugs.com while Drugstore.com offers the same product and dose for $119.99?

The answer is good American capitalism.  No, not in the way you think. Pharmaceutical Companies are not charging more in the US simply because they can.

Pharma Companies are obliged to charge less for the same product in every “G-7” (Group of 7) industrialized nation countries (Canada, France, Germany, Italy, Japan, the United Kingdom) except for the United States (see Table for examples).

Drug Pricing in Canada
In Canada, the Patent Medicine Prices Review Board establishes and enforces guidelines that determine the maximum prices at which manufacturers can sell brand name drugs. The Canadian pricing system results in brand name drug prices that are an average of 38% lower than prices in the US

Drug Pricing in France
The French pricing system allows pharmaceutical companies to sell their products at any price. However, if these companies want the national health care system to reimburse patients for the cost of the drug, the companies must agree to a lower, negotiated price. The French pricing system results in brand name drug prices that are an average of 45% lower than prices in the US

Drug Pricing in Italy
Italy’s national health care system allows manufacturers to sell their drugs at any price.
However, if these drugs are to be eligible for reimbursement under the national health care system, pharmaceutical companies must set the price of the drug at a cost that does not exceed a twelve country European average price. The Italian pricing system results in brand name drug prices that are an average of 48% lower than prices in the US.

Drug Pricing in the United Kingdom
Drug companies in the United Kingdom are free to establish their own prices for individual drugs. However, under the country’s pharmaceutical laws, the maximum profit that drug manufacturers can earn on sales in the United Kingdom is limited. The pricing system in the United Kingdom results in brand name drug prices that are an average of 31% lower than prices in the US.

Reference: http://oversight.house.gov/documents/20040629103247-74022.pdf

The fact is that price controls in 6 of the G7 nations places an undue strain on the US consumer.

To put it in simple terms, the US (about 300 million people) subsidize R&D for the other six G7 countries (about 425 million people). That doesn’t seem fair to me.

Having been born and raised in what we now call a “Developing Economy” (we used to be known as 3rd world counties), I recognize that adjustments must be made to factor economic conditions.  However, industrialized nations should be able to equitably share in the development of life-saving therapies.

Unfortunately, drug re-importation proposals by both Presidential candidates seek to address the symptom, not the cause.

Forcing Pharmaceutical companies to artificially lower the cost of drugs in the US will have a negative impact on their ability to bring new and life-changing products to market.  And that hurts us all. 

In my opinion, we should seek to address the root cause of higher prescription drug costs in the US.  To this end, every G7 nation should equitably share in the cost of R&D for pharmaceutical drugs. That would bring prices down in the US, while supporting the development of new and innovative Pharmaceutical therapies.

20Oct/08

Presidential Candidates Agree on Drug Re-Importation – That is Not Fair

By Daniel R. Matlis

Although Senators McCain and Obama (listed in alphabetical order) are looking to address many of the same problems, they have very different approaches.

The Presidential candidates don’t agree on many things, from the economy to energy, healthcare to taxes, even Joe the Plumber.

One thing they both agree on: Drug Re-importation.

John McCain will look to bring greater competition to our drug markets through safe re-importation of drugs and faster introduction of generic drugs.

Barack Obama and Joe Biden will allow Americans to buy their medicines from other developed countries if the drugs are safe and prices are lower outside the U.S.

I thought it would be worth discussing some facts about drug re-importation:

FACT: You can buy many pharmaceutical drugs abroad for a lower price.
FACT: Some of these drugs are made by the same company at same plant, to the same standards as those sold in the US.

So why is a 30 day supply of 20mg Lipitor available for $60.78 on CanadaDrugs.com while Drugstore.com offers the same product and dose for $119.99?

The answer is good American capitalism.  No, not in the way you think. Pharmaceutical Companies are not charging more in the US simply because they can.

Pharma Companies are obliged to charge less for the same product in every “G-7” (Group of 7) industrialized nation countries (Canada, France, Germany, Italy, Japan, the United Kingdom) except for the United States (see Table for examples).

Drug Pricing in Canada
In Canada, the Patent Medicine Prices Review Board establishes and enforces guidelines that determine the maximum prices at which manufacturers can sell brand name drugs. The Canadian pricing system results in brand name drug prices that are an average of 38% lower than prices in the US

Drug Pricing in France
The French pricing system allows pharmaceutical companies to sell their products at any price. However, if these companies want the national health care system to reimburse patients for the cost of the drug, the companies must agree to a lower, negotiated price. The French pricing system results in brand name drug prices that are an average of 45% lower than prices in the US

Drug Pricing in Italy
Italy’s national health care system allows manufacturers to sell their drugs at any price.
However, if these drugs are to be eligible for reimbursement under the national health care system, pharmaceutical companies must set the price of the drug at a cost that does not exceed a twelve country European average price. The Italian pricing system results in brand name drug prices that are an average of 48% lower than prices in the US.

Drug Pricing in the United Kingdom
Drug companies in the United Kingdom are free to establish their own prices for individual drugs. However, under the country’s pharmaceutical laws, the maximum profit that drug manufacturers can earn on sales in the United Kingdom is limited. The pricing system in the United Kingdom results in brand name drug prices that are an average of 31% lower than prices in the US.

Reference: http://oversight.house.gov/documents/20040629103247-74022.pdf

The fact is that price controls in 6 of the G7 nations places an undue strain on the US consumer.

To put it in simple terms, the US (about 300 million people) subsidize R&D for the other six G7 countries (about 425 million people). That doesn’t seem fair to me.

Having been born and raised in what we now call a “Developing Economy” (we used to be known as 3rd world counties), I recognize that adjustments must be made to factor economic conditions.  However, industrialized nations should be able to equitably share in the development of life-saving therapies.

Unfortunately, drug re-importation proposals by both Presidential candidates seek to address the symptom, not the cause.

Forcing Pharmaceutical companies to artificially lower the cost of drugs in the US will have a negative impact on their ability to bring new and life-changing products to market.  And that hurts us all. 

In my opinion, we should seek to address the root cause of higher prescription drug costs in the US.  To this end, every G7 nation should equitably share in the cost of R&D for pharmaceutical drugs. That would bring prices down in the US, while supporting the development of new and innovative Pharmaceutical therapies.

11Sep/08

Please Do The Right Thing Even When No One is Looking

By Daniel R. Matlis

On September 15 2008, FDA’s final rule on “Current Good Manufacturing Practice and Investigational New Drugs Intended for Use in Clinical Trials” will become effective.

The Rule makes “early phase 1 clinical drug development safe and efficient by enabling a phased approach to complying with current good manufacturing practice (cGMP) statutes and FDA investigational requirements.”  Additional detail is available in the FDA’s Companion Guidance Document.

Phase 1 trials are used as the initial introduction of an investigational new drug into humans. These studies are closely monitored and may be conducted in patients, but are usually conducted in healthy volunteer subjects. These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. Phase 1 clinical trials, are often carried out in small-scale, academic environments, typically involving fewer than 80 subjects (many of them college students).

The rational for exempting most phase 1 investigational drugs from the requirements in 21 CFR § 211 (cGMP) is based on the premise that since most products do not proceed beyond the clinical trial phase of development, the burden of full compliance with cGMP at the phase 1 stage outweighs the benefits.

According to Rachel Behrman, M.D., associate commissioner for clinical programs and director of FDA’s Office of Critical Path Programs, “The new rule and guidance are intended to assure that manufacturers meet high standards for the safety of phase 1 drugs and biologics while removing unnecessary barriers that can slow the development of these potentially life-saving products.”

The FDA will continue to exercise oversight of the manufacture of these drugs under FDA’s general statutory CGMP authority and through review of investigational new drug (IND) applications.

I asked a friend, who is Director of R&D and product development at a large Pharma company in Central New Jersey, to review this article before publication. She commented that: “There may be a balance or even some good that this will do to expedite the process and invest the cost savings elsewhere, which may add value in the long run.  The entire drug development process is very costly and very unpredictable, but to your point, patient safety needs to be at the forefront.”

The fact is that bringing a new drug to market is a time consuming and expensive process. According to latest estimates it on average 12 to 15 years to bring a drug to market (See Figure)
The cost for bringing a new drug to market, that is from discovery to FDA approval, hovers around 1 Billion (yes with a B) dollars.

As we globalize and outsource development and manufacturing, it is critical to bear in mind that while mature sponsor organizations will often “do the right thing” even they are not obliged,   these expectation are not always met by operating practices at “less than mature companies or those in economies” (do Heparin and  Rambaxy ring a bell)

In the current drive to outsource, clinical manufacturing is a reasonable and viable development avenue. According to Jeffrey Meltzer, Director of Quality Management at Pharmaceutical Manufacturing Research Services Inc., “a key challenge of this approach is that some people and organizations think manufacturing outsourcing means that they are also outsourcing responsibility.” Meltzer added, “The implementation of this final rule makes it even more critical to partner with a mature, well established contract organization that has in place systems to confirm mutual expectations including contractor and sponsor responsibility.”

Failure to establish appropriate procedures and controls over Phase 1 manufacturing may in fact delay drug development and make it more costly. “Sure, you may get your Phase 1 done a bit faster and cheaper, but if the work is not well documented and well controlled, it increases the risk of incorrect development decisions” commented Meltzer.

My R&D Director friend at the Big Pharma Company (who shall remain nameless) pointed out that I seem pessimistic.  She is right I am a bit concerned about this rule, especially as we outsource to less mature markets. 

This concern stems from the experience that individual and organizational responses to regulatory compliance fall into four categories. (See Regulatory Compliance – Nature or Nurture?)

In my experience, many regulatory Zealots and Rationalist are in mature companies, for whom “Thou Shalt Do The Right Thing Even If Not Obliged” has been ingrained into the fabric of the organization. On the other hand, I have a sense that you would find many more Contrarians and Illusionned at less mature organizations.

Although the vast majority of Life-Science companies will do the right thing even if there is no regulatory requirement to oblige them. I am afraid that for some, aggressive development timelines and short term financial pressures may trump patient safety, especially where “doing the right thing” is not a core value.

This is one time when I hope I’m wrong. Because as the adage goes, there is never enough time to do it right, but there is always time to do it over.

In our industry, the consequences of a do-over can be life-threatening.

So please, do the right thing even when no one is looking.

28May/08

Obecalp Is Clinically Proven More Effective Than Hugs and Kisses

By Daniel R. Matlis

For years I have been joking about some company marketing a sugar pill based on clinical trial data supporting the “placebo effect”.

I never thought I would see the day when this prediction would come true.

Well, today is the day. Efficacy Brands LLC has begun selling Obecalp “…the First Standardized Branded and Pharmaceutical Grade Placebo…”

Jennifer Buettner, the brains behind Obecalp, offers this rational for the product. “Children, adults and seniors shouldn’t be given any type of drug when one is not needed. Until I invented Obecalp there weren’t any options. Now, with Obecalp, the medical authority figure, whether it be a doctor, nurse, or mommy can decide if medicine is needed. If not, Obecalp might just be the answer.” (Why can’t dad be the medical authority figure?)

I could not believe my eyes when she added, “Manufacturing Obecalp with the cGMP process assures our consumers that they are purchasing the finest pharmaceutical grade placebo.”

Wow, where do I start… This is wrong is so many ways.

Asserting to follow cGMPs to manufacture a sugar pill designed to do nothing?  Nice marketing!!!

I agree that we should not give children or adults medicines they don’t need.  So instead, we should lie to them and tell them that a sugar pill will make them better?

What’s the message we are conveying to the next generation?  A pill can solve all your problems? (I know, we have not made pills in a long time, we now make tablets, caplets, gel-caps, etc.)

When one of my children gets a boo-boo, I have found that “kissing the boo-boo better” works in the vast majority of cases.  When that doesn’t, I escalate the treatment to hugs and kisses.

And if I have to resort to sugar to make them feel better, I provide it in the form of a “non cGMP manufactured” lollypop or USDA regulated ice-cream.

The sad part of the story is that, at a reported $5.95 for 50 tablets, Efficacy Brands will probably make lots of money selling Pharmaceutical Grade Placebo tablets.

XOXO anyone?