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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.

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.

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?

By Ronald L. Trowbridge, Ph. D.
Volunteer Adjunct Scholar
Abigail Alliance for Better Access to Developmental Drugs

In August, we (Abigail Alliance) lost our case in the D. C. Circuit Court of Appeals.  We are appealing this decision to the Supreme Court.  We argue that terminal patients with no options left but death have a constitutional right to promising investigational drugs already proven safe enough for further testing on people, in the care of a qualified physician.

Recently my partner Steve Walker and I conducted painstaking research that disclosed appalling findings.  We collected data from the FDA, the American Cancer Society, and from a number of research oncologists expert in their respective fields of cancer indication and corresponding drug response.  We focused on the 12 promising investigational drugs that the Alliance had pushed for early access over the past five years, all of which were subsequently approved by the FDA.

In sum, these 12 drugs—had they been available to people denied entry to clinical trials—would have helped well over one million people live extended lives, anywhere from a few months to many years.

Generally, our critics cite four lines of opposition:

1. Our proposal would open a floodgate to quack drugs on the market.  Not true for two reasons:  one, the promising drugs we promote must clear at least Phase I of FDA testing and control; two, a qualified physician must officially prescribe these drugs for individual patients.

2. Our proposal would cause a maelstrom of confusion in record-keeping, given responses to limited patients in clinical trials and responses of unknown thousands of terminal patients to investigational drugs.  But if we can get a man to the moon, we can design software systems that will separately track clinical-trial patients as well as terminal patients getting investigational drugs.  Establishing such dual systems will take diligence, especially at the outset, but it’s doable and worth the effort: extending human lives.

3. Our proposal will harm some terminal patients.  This argument is incredulous, because it says to the terminal patient:  “This drug might not be safe for you, so we won’t let you take it.  You can go ahead and die, but you’ll be safe from the drug.”  As Orwell said in 1984 on doublespeak, war is peace, hate is love, and terminal death is safety.  Let the decision to take a promising investigational drug be between the qualified physician and patient, informed of the risk.

4. Our proposal will discourage patients from entering clinical trials.  Three responses here:  one, our proposal speaks only of terminal patients denied access to clinical trials.  Two, patients will seek the best odds for survival, and why not? Three, the FDA acknowledged in its own legal brief:  “the number of persons who are accepted for participation in clinical trials is relatively small . . . . The number of qualified would-be participants may exceed the number of spaces in the trials.”

This fall the ACCESS Act will be introduced in the House and Senate legislating our proposal.  The Act will permit promising investigational drugs, still regulated by the FDA, to be prescribed to terminal patients.

Dr. Trowbridge was Chief-of-Staff to Chief Justice Warren Burger and the Commission on the Bicentennial of the U. S. Constitution.  Before that, he was appointed by President Reagan, with unanimous confirmation by the U. S. Senate, to a top-level administrative position at the United States Information Agency.  He holds a Ph. D. in English from the University of Michigan.

By Daniel R. Matlis

No, it’s not what you think; I’m not going “pro” this or “anti” that on you.

I am referring to the Food and Drug Administration’s (FDA) proposal to make experimental drugs widely and easily available to seriously ill patients.

According to Dr. Andrew C. von Eschenbach, Acting FDA Commissioner “This proposed reform is carefully designed to balance several objectives.” von Eschenbach added “One goal is to enable many more patients who lack satisfactory alternatives to have access to unapproved medicines, while balancing the need for safeguarding the individual patient. Another equally important goal is to ensure the continued integrity of the scientific process that brings safe and effective drugs to the market.”

The proposed rule is a direct response to a 2 to 1 decision by the U.S. Court of Appeals for the District of Columbia Circuit overturning a lower court’s ruling in a case brought by the Abigail Alliance for Better Access to Developmental Drugs.

The court ruled that “barring a terminally ill patient from the use of a potentially life saving treatment impinges on the right of self-preservation.” Further, the court held that once drugs have passed safety trials, they should be made available if they might save someone’s life.

Judge Judith W. Rogers wrote “If there is a protected liberty interest in self-determination that includes a right to refuse life-sustaining treatment, even though this will hasten death, then the same liberty interest must include the complementary right of access to potentially life-sustaining medication, in light of the explicit protection accorded ‘life’.”

Dr. Janet Woodcock, FDA’s Deputy Commissioner for Operations stated “FDA hopes this proposal will increase awareness in the healthcare community of the range of options available for obtaining experimental drugs for seriously ill patients,” she added that “By clarifying and streamlining the processes, FDA also hopes to encourage companies to make such drugs available, and reduce barriers for healthcare practitioners in obtaining them.”

The proposed rules, which are open for comment for 90 days, are described in detail at the following FDA web address: http://www.fda.gov/cder/regulatory/applications/IND_PR.htm

I hope and pray that none of us ever face such a choice, but if we do, it should be our choice to make.

By Daniel R. Matlis 

According to a report issued by the Institute of Medicine (IOM), the FDA suffers from a lack of clear regulatory authority, chronic under funding, organizational problems, and a scarcity of post-approval data about drugs’ risks and benefits.  

The report, entitled “The Future of Drug Safety: Promoting and Protecting the Health of the Public”, was commissioned by the FDA and the Department of Health and Human Services in response to the growing public concern with health risks posed by approved drugs. The Agency asked the IOM to convene a committee to assess the U.S. drug safety system and to make recommendations to improve risk assessment, surveillance, and the safe use of drugs. 

“FDA has an enormous and complex mission — both to make innovative new drugs available to patients as quickly as possible and to assess the long-term risks and benefits of these products once they are on the market,” said Sheila Burke, chair of the committee that wrote the report.  “We found an imbalance in the regulatory attention and resources available before and after approval.  Staff and resources devoted to pre-approval functions are substantially greater.  Regulatory authority that is well-defined and robust before approval diminishes after a drug is introduced to the market.  Few high-quality studies are conducted after approval, and the data are generally quite limited.  Many of the report’s recommendations are intended to bring the strengths of the pre-approval process to the post-approval process, to ensure ongoing attention to medications’ risks and benefits for as long as the products are in use.” 

During its research, the committee found that

1. There is a perception of crisis that has compromised the credibility of FDA and of the pharmaceutical industry.
2. Most stakeholders–the agency, the industry, consumer organizations, Congress, professional societies, health care entities–appear to  agree on the need for certain improvements in the system.
3. The drug safety system is impaired by the following factors: serious resource constraints that weaken the quality and quantity of the science that is brought to bear on drug safety; an organizational culture in CDER that is not optimally functional; and unclear and insufficient regulatory authorities particularly with respect to enforcement.
4. FDA and the pharmaceutical industry do not consistently demonstrate accountability and transparency to the public by communicating safety concerns in a timely and effective fashion. 

To address these issues, the report offers a broad set of recommendations to ensure that consideration of safety extends from before product approval through the entire time the product is marketed and used.  
These recommendations include:

• Labeling requirements and advertising limits for new medications
• Clarified authority and additional enforcement tools for the agency
• Clarification of FDA’s role in gathering and communicating additional information on marketed products’ risks and benefits 
•  Mandatory registration of clinical trial results to facilitate public access to drug safety information
• An increased role for FDA’s drug safety staff
• A large boost in funding and staffing for the agency

“We have already called for making sure the FDA has adequate resources to perform its critical drug review, surveillance and monitoring functions: said Caroline Loew, Senior Vice President of the Pharmaceutical Research and Manufacturers of America (PhRMA), “Additionally, PhRMA supports recommendations for modernizing the post-market surveillance system for drugs, including more efficient use of the adverse reaction reporting system; maximizing use of large health care data bases; and building more expertise around epidemiological studies.”

I agree that the FDA and Industry need to do a better job monitoring medications’ risk-benefit profiles after approval. They must also improve communications to healthcare providers and patients on the uncertainties and potential risks associated with newly introduced drugs. 

However, as patients, we must recognize that there are no “risk free medicines”. Each patient must work with their healthcare provider to evaluate the risk-benefit profile associated with each recommended therapy and make an informed decision based on the facts available at that time. We must also remain vigilant and be ready to reassess those choices when new post approval data becomes available.

After all, our health is our responsibility.

By Daniel R. Matlis

Recently, I wrote an article calling for consistent federal regulatory requirements for the practice of compounding. Last month, the US District Court in Texas ruled against the FDA on this mater.
 
As I made clear in my previous article, I am a supporter of compounding. But in order to protect the public, it is imperative that the combination of FDA approved drugs into new compounds be tested for safety and effectiveness.
 

Critics may ask: Don’t two FDA approved compounds a safe new compound make? 

Not always. Remember Fen-Phen?

Fen-Phen is the combination of fenfluramine or dexfenfluramine (marketed as Redux) and phentermine. All were prescription medications approved by the FDA as appetite suppressants. In 1996, physicians began prescribing the combination of Fen-Phen for use in weight loss programs. During that year, the number of prescriptions for Fen-Phen in the United States exceeded 18 million. The practice is known as “off-label use” since no studies are presented to the FDA to demonstrate the effectiveness or safety of the drugs taken in combination. 

In July 1997, the New England Journal of Medicine published an article potentially linking heart valve disease with the use of Fen-Phen.  Later in that year, the FDA found that of 291 asymptomatic patients screened, about 30 percent had abnormal valve findings, primarily aortic regurgitation. Based on these data, the manufacturers agreed to withdraw the products from the market and FDA recommended that patients stop taking the drugs.

But this is not a recent phenomenon. In 1937 the manufacturer of “Elixir Sulfanilamide” was seeking a palatable solvent for its new sulfa drug. It decided to use a combination of diethylene glycol and water with raspberry flavoring.  Both the drug and the solvent are safe by themselves, but combined create they a lethal mixture that killed 107 people (mostly children) before the drug was recalled recalled.  Similar to Fen-Phen the combination compound had not been tested prior to release to the public. 

By contrast before the introduction of Caduet, the combination of high blood pressure medicine Norvasc and high cholesterol Lipitor, the manufacturer conducted a double blind placebo controlled clinical trial of 1660 patients to evaluate the safety of the combination therapy.

I believe there are two approaches to address this issue; the first is to required safety testing for new compounds comprised of already approved drugs, regardless of who makes them, big Pharma or your neighborhood pharmacist.  This testing should focus on the safety and efficacy of the new compound. 

The second alternative is to go the route of informed consent and experimental drugs.  I believe that doctors should have the right to prescribe compounded medicines, pharmacist the right to make then and patients the right to take them as long as we can evaluated all known risks and have meaningful  informed consent.

By the way, I checked with Andrew, my neighborhood pharmacist, and he will only mix in flavor for my kids prescriptions if the drug has been tested for safety in combination with the flavoring syrup.

This week, Scott Gottlieb, MD Deputy Commissioner for Medical and Scientific Affairs at the Food and Drug Administration made an interesting speech before the 2006 Conference on Adaptive Trial Design in Washington, DC.Dr Gotlieb commented how today’s clinical trials are highly empirical. Drugs are tested on general populations for a response and a treatment effect that is statistically not likely to be a chance result. This approach is rigorous and focused, but inflexible. According to Dr. Gotlieb, “another problem with the empirical approach is that it yields statistical information about how large populations with the same or similar conditions are likely to respond to a treatment. But doctors don’t treat populations, they treat individual patients. Doctors need information about the characteristics that predict which patients are more likely to respond well, or suffer certain side effect. The empirical approach doesn’t tell doctors how to personalize their care to their individual patients.” This results in a highly empirical approach to the practice of medicine. Gone are the days of: Take two off these and call me in the morning. Gottlieb comments “Doctors prescribe treatments knowing full well that only a certain percentage of their patients will receive a benefit from any given medicine.” This approach is akin to: Take all of these and call me if you have a side-effect. 

But with the demands for personalized medicine and the advent of Pharmaco-genomics, there are potentially better alternatives. By enabling more trials to be adapted based on knowledge about gene and protein markers or patient characteristics, we can help predict whether patients will respond well to a new medicine. “These new approaches to clinical trials can result in trial designs that tell us more about safety and benefits of drugs, in potentially shorter time frames, exposing fewer people to experimental treatments, and resulting in clinical trials that may not only be more efficient but are more attractive to patients and their physicians to enroll in.” said Gottlieb. This is only a first step in the process to develop more adaptive clinical trials. This process will lead to more targeted therapies and in turn, Ii is my hope, more personal and personalized medicine.

During my senior year, I was lucky to have a few job offers to evaluate. The top two were from Johnson & Johnson and Exxon. As part of my research I looked at how each company handled adversity. For me it was an easy choice when I compared J&J’s handling of the Tylenol situation vs. Exxon’s Valdez.  I was drawn by the impact I could make in people’s lives and by the industry’s reputation in general and J&J’s in particular.

But in recent years, our industry has gone though some tough times. We’ve have seen record FDA fines, product recalls and withdrawals as well as the erosion of consumer confidence.  In my opinion executives at some Life-Science companies lost focus on the patient and began to concentrate on profits for Wall Street.

It is in times like these that we must reach for our roots and reflect on the legacy left by our industry’s founders.

In the August 1952 Time magazine interview, George W. Merck said “Medicine is for people, not for profits.” He went on “…if we remembered that, the profits have never failed to appear. The better we remembered, the larger they have been.”

In 1943 General Robert Wood Johnson wrote: “We believe our first responsibility is to the doctors, nurses and patients, to mothers and fathers and all others who use our products and services.” This Credo is still etched in stone at the J&J world Headquarters.
In 1899 Charles Pfizer said, “Our goal, has been and continues to be the same: to find a way to produce the highest-quality products and to perfect the most efficient way to accomplish this, in order to serve our customers. This company has built itself on its reputation and its dedication to these standards, and if we are to celebrate another 50 years, we must always be aware that quality is the keystone.”

In this post Sarbanes-Oxley era, I am heartened to see that our industry is once again putting patients first.

Let us remember to chase after the cures for human ailments, then and only then will fair profits follow.

By Daniel R. Matlis

The American Medical Association’s new policy on Direct to Consumer Advertising includes imposing a temporary moratorium on newly approved drugs and guidelines for pharmaceutical companies to follow when preparing DTC advertising.

AMA President-elect Ronald M. Davis, MD said “A temporary moratorium on DTC advertising of prescribed drugs and medical devices will benefit both the patient and physician.” He added “Physicians will have the opportunity to become better educated on the pros and cons of prescription drug uses before prescribing them, and will be better able to determine when they are best suited for their patients’ medical needs.”

The AMA suggested the following guidelines for DTC ads:

• provide objective information about drug benefits that reflect drug efficacy, as determined by clinical trials
• show fair balance between the benefits and risks of the advertised drugs by providing comparable time or space and cognitive accessibility, and by presenting warnings, precautions and potential adverse reactions in a clear and understandable way without distraction of content
• clearly indicate that the ad is for a prescription drug and refer patients to their physician for more information and appropriate treatment
• target age-appropriate audiences
• should receive pre-approval from the FDA

“The AMA will work with the pharmaceutical industry for universal acceptance of the guidelines so that physicians can help patients obtain appropriate medications” said Dr. Davis.

Let’s see how the FDA and PhRMA respond.