In today’s healthcare environment, with the internet and media coverage providing early stage insight into developmental pipelines, more and more physicians and patients are calling for access to drugs before they are approved for marketing.  However, it’s not always the FDA that stands in the way.  The drug companies also have to agree to provide their developmental products for special access. For various reasons, they are not always willing to do it. 

The treatment of a seriously ill patient with an unapproved drug is often referred to as “compassionate use”.  The FDA has had regulations in place for the compassionate use of drugs since 1987.  In the U.S., when a patient is not able to enroll in a manufacturer-sponsored clinical trial, the patient has two options to obtain access to an investigational product: (1) an expanded access program or (2) single patient access by special/compassionate exemption. 

With an expanded access program (EAP), the sponsor (the drug manufacturer or a health organization such as the National Cancer Institute) must apply to the FDA to provide special access to a group of patients.  The EAP is conducted as a research protocol in a clinical setting such as a doctor’s office or university research facility.  This type of program is typically offered in the later stages of clinical trials when the safety and efficacy of the product have been fairly well established.  In addition, an EAP works well when the patients live in the same general area near the research facility.

If no EAP is offered by the sponsor (e.g. for drugs used to treat rare diseases) or the patient is not eligible for an EAP due to program criteria, location or other factors, then the patient’s physician may apply for a special exemption.  First, the doctor must get the drug company on board. Then, the doctor, with assistance from the drug company, applies to the FDA for authorization to provide the drug to the patient.

The FDA states that it rarely blocks access to unproven medications for those with serious illness; however, it does reserve the right to reject applications for special access when it feels that the drug is not safe (even if the patient is already dying).  While the FDA does sometimes reject requests for compassionate use, it is often the drug manufacturers that withhold their products.  Compassionate use programs can be very expensive and time-consuming.  The companies are under no legal obligation to provide access to the drugs, and the FDA has no authority to compel the pharmas to offer EAP’s or single patient access. 

Some of the reasons that a drug company may choose not to offer a compassionate use program are:  

• The company’s ultimate goal is to get the product approved for marketing. Compassionate use programs divert time and resources away from achieving this goal.
• Compassionate use regulations can be complex and different from country to country. The regulatory affairs department must be prepared to wrestle with these regulations or the company must pay an outside vendor to deal with the health authorities.
• The company must take on additional costs to manufacture, distribute and track the product.
• The company must perform pharmacovigilance in order to monitor the products safety and efficacy as well as track, assess and report adverse events.
• These programs cannot be promotional in any way. Companies are not able to solicit patients and physicians without heavy fines.
• The drug is often offered free-of-charge to the patients as part of the program. Thus, there may not be any money coming in to recoup the costs of the program.
• In the end, the product may not be approved. Why go above and beyond the clinical trials that are already required?

On the other hand, drug companies are starting to realize that compassionate use programs provide a number of benefits.  First and foremost, these programs help patients that are in desperate need for treatment.  This should be priority #1 for drug manufacturers.  Other benefits include: 

• If the manufacturer does not provide access to product, patients may use other means to get their hands on it. These programs give manufacturers tighter control over the patient population and the distribution network.
• While these programs are not a replacement for clinical trials, they provide additional real-world safety data over clinical trials alone.
• The programs allow a company to get into a market earlier than usual. The patients that participate in the program remain patients (customers) after the product goes to market.
• Physicians and opinion leaders get involved earlier in the development process. They become the initial adopters that build industry confidence in the product and accelerate growth once the product is approved. This is especially important in countries where the manufacturer may not have existing relationships within the healthcare arena.
• The company will have a better idea how to market the product. It will have a more complete understanding of the customers and their needs.

While the public perception is that the FDA restricts access to experimental products, the arguments above contend that this is not always the case.  The FDA has provided a framework for compassionate use programs, but this framework relies on the willingness of drug companies to provide access to their drugs.  And unfortunately, the reward of compassionate use programs often does not always outweigh the risk. Perhaps more incentives are needed? Or streamlined processes around compassionate use programs? 

What do you think?  Your thoughts are welcome.

There are a number of strategies that the brand-name manufacturers have employed since the Hatch-Waxman Act in 1984 in order to stave off generic manufacturers and retain market exclusivity.  The most common tactic is a combination of “evergreening” and aggressive litigation.  With evergreening, the company stockpiles patents on as many aspects of the product as possible.  When a generic company attempts to get marketing authorization, the brand-name manufacturer takes the generic company to court over claimed infringements with some patented aspect of the product.  This allows the drug manufacturer to delay the entry of competition and retain its big profits (for up to 30 months or longer in the U.S.).

However, litigation is only a short-term strategy - eventually the generic drug makers will enter the market.  Other tactics meant to invoke a more gentle decrease in product price once the generics invade are: 

• Patents on new formulations / combinations - Coming up with better delivery methods, simpler administration routes (e.g. once a day versus three times a day), combination products and new isometric forms may stifle competition and keep doctors and patients coming back to the brand name
• Patents on improvements in the manufacturing process in order to decrease costs
• Aggressive advertising campaigns to keep their products fresh in the minds of doctors and patients. In addition, brand-name manufacturers jump on every opportunity to promote bad press about unexpected adverse events with generics (i.e. the heparin from China fiasco) or poor manufacturing controls (such as the FDA ban of 30 generics from Ranbaxy). These negative advertising campaigns are meant to scare consumers aware from generics.

Lately though, the market is starting to take a different turn. In a number of ways, the brand-name manufacturers are starting to play more of a hand in the generics market. 

• Some brand-name manufacturers have begun marketing their own “authorized generic” to compete with the first generic manufacturer to gain entry. This may be done through a subsidiary or through a licensing deal with another generic manufacturer. The brand-name manufacturer gets a slice of the pie while decreasing the profits for the first generic competitor. When paired with the delays and costs of an aggressive litigation campaign from the brand-name company, the generic drug maker may be deterred from entering the market at all.
• A number of big pharmas have started purchasing generic companies. This serves three purposes: (1) it allows the brand-name company to launch their own “authorized generics” through a subsidiary that is better suited for the generic business, (2) it enables brand-name manufacturers to have a presence in countries that cannot yet afford brand-name prices - such as Brazil - and (3) it decreases competition, allowing prices and profits to remain higher. This has started a domino effect as big generic companies are forced respond in kind - case in point: Teva’s recent purchase of Barr Pharmaceuticals.
• In some recent cases, the brand-name manufacturer has resorted to financial arrangements - or what some may call payoffs - in order to stifle competition. For example, see Pfizer’s settlement with Ranbaxy to delay their generic version of Lipitor by 20 months. While these arrangements may violate antitrust laws, the government has not levied any punishments yet.

So while the percentage of drug prescriptions dispensed for generics has steadily increased over recent years, the brand-name manufacturers have been able to keep their percentage of sales fairly high (84% in 2007, down from 88% in 1999).  Surely, this battle will continue to rage on for years to come. Hopefully, the generic industry will be strong enough to keep prices affordable for consumers, while the brand-name drug makers get enough market share to continue to bring innovative products to patients. Balance will be the key.

According to the FDA, in order to be considered a “botanical” product, a drug must have the following characteristics:

• A botanical drug product consists of vegetable materials, which may include plant materials, algae, macroscopic fungi, or combinations thereof.
• A botanical drug product may be available as (but not limited to) a solution (e.g., tea), powder, tablet, capsule, elixir, topical, or injection.
• Botanical drug products often have unique features, for example, complex mixtures, lack of a distinct active ingredient, and substantial prior human use. Fermentation products and highly purified or chemically modified botanical substances are not considered botanical drug product. (1)

Headquartered in Jamesburg, NJ, Phytomedics was launched in 1996 to focus on such botanical drug products and has partnered with the Biotech Center at Rutgers University for its research and development, allowing it to function as a private company with access to cutting-edge research facilities while keeping its costs low. Those costs are being covered by several investment firms including Inventages Venture Capital GmbH (life ventures by Nestle), Burrill & Company, Polar Investments Ltd and Biotech M.A.H. Plant Genomic Fund.

The company currently has 2 drugs in development. The first, which has already commenced its Phase III clicnical trial development, is a new, oral drug for treatment of auto-immune diseases. In its Phase II, double-blind clinical trial, PMI-001 was given to 120 patients with moderate to severe rheumatoid arthritis. The results showed significant efficacy of the drug, with rapid pain reduction in as little as 2 weeks and a halt in joint erosion in 6 months. PMI-002 is the second botanical drug under development and shows promise in the treatment of cancerous cells as well as the possible prevention of neurological and opthalamic degenerative disorders.

Other drugs are also in their pipeline, but have not yet received the same focus as their other products (it seems due to lack of funding). These products include:

• A botanical bioactive that acts as a COX-2 inhibitor but with less risk than a Vioxx, Celebrex or other synthetic chemical entity.
• A botanical appetite suppressant that could be leveraged for weight loss, and a counterpart derived from an agricultural waste processing stream that could block fat absorption.
• A plant-derived agent that could be used to limit the impact of aging on muscle cells.

It seems that these drugs, along with the proprietary methodologies the company is using to develop them, could usher in a new wave of drugs that will be prescribed by doctors in the future. As you may know if you’ve read a few of my posts, I’m very interested in keeping an excessive amount of “artifical” stuff out of my body, and the research here shows promise for drugs that may be headed in that direction. I am hopeful that companies like Wellgen and Phytomedics can provide breakthroughs in this area of research and demonstrate the safety and efficacy of these drugs because of their origins as completely natural substances.

However, until an actual product has been released and clinical trials can demonstrate the safety of the product and its interaction in the human body can be better understood, I remain cautious of drugs developed within this emerging field.

Your thoughts?

(1) See “What is a Botanical Drug?“, FDA web site.

I believe at some point in my life I will need glasses. I’ve been lucky so far, being nearly 34 and having avoided them thus far, but if family history dictates the need, then I’ll probably need a pair sometime in my early 40s (or, with denial, late 40s). I wonder if I’ll opt for LASIK eye surgery, the popular surgery used to correct vision problems. As I write this, I’m checking out the FDA web site describing the procedure and the risks associated with it, and wonder how the procedure and studies will change by the time I need to consider it.

But that’s not what I’m focused on tonight. Long before I lose my vision, I’ll squint to read. Squinting will contribute to the wrinkles that I can already see forming around my eyes. Wrinkles that mean I’m getting old.

I know that my concern about staying young only plays into the increasing obsession we have in America with keeping people guessing as to how old we are. We want to look good for our age, as opposed to looking aged. And we are so desperate to retain our youthful looks that we’ll put our own bodies at risk with extreme makeovers, which can include broken bones radical surgical procedures.

Botox, an injectable serum made from the botulism toxin and produced by Allergan, Inc., is somewhat less radical than surgery but shown to be effective and popular for treating wrinkles. While I admit I’ve been curious about this drug and how it works, I read today that the FDA announced this week that they’re reviewing the safety of Botox.

While the base toxic ingredient is normally lethal to humans, drug maker Allergan has concocted a dose that can be used to target a specific muscle or group of muscles and render it essentially immobile by its application. The drug appears to be relatively benign in cases where it’s used for its intended cosmetic uses. Problems seem to arise, however, when doctors prescribe it for off-label uses, that is, medical applications of the drug not yet approved by the FDA. Most commonly, Botox is applied in these cases as treatment for limb spasms in cases of cerebral palsy and for treating cervical dystonia, or rigid neck muscles. These also, however, were the cases that had reported adverse events, the most serious of which occurred in children.(1)

The article goes on to indicate that problems likely occurred because of over use and overdosing of the medication, and the likelihood that any adverse reaction would occur in a cosmetic application are slim. Still, the article warns that people should pay attention to symptoms that could be related to botulism, such as weakness or trouble swallowing or breathing.

I would love to be forever young, and take advantage of my youth all over again. As I look at myself in the mirror every day, I see changes in my body that indicate I’m no longer the 20-year-old that looked back. The hair is thinning, the wrinkles are starting to form, although I have to squint now to actually see them. What might I be willing to do in order to recapture some of that youth that is slowly melting away before my very eyes?

Then again, I look at the things that make me feel young without the use of any drugs; my son and my wife. The days that are most special, the days that I can cling to unlike my thinning hair, are days when he points to my MP3 player, asks for music, and insists that my wife and I dance with him as he makes up his own dance moves reminiscent of the southern Italian Tarantella.

And I don’t need to squint to see it.

(1) See “FDA reviewing safety of Botox and rival product,” Lisa Richwine, Reuters, Feb 8, 2008.

As one might think, the FDA has a process for approving and rejecting drugs sold in the United States. From what I remember from my days working at one of the large pharmaceuticals as a consultant in their regulatory department, few drugs are actually rejected; companies don’t even want to risk rejection, because costs to correct problems and then re-apply for approval can be high, and there’s probably a certain amount of stigma attached to a drug that had been rejected its first time around. Approved drugs, on the other hand, have reached the holy grail of the process, and can start showing returns for the millions of dollars that have been spent to develop and market them. However, there is a recent trend of “approvable” letters that are being sent out in larger numbers from the FDA in response to new drug applications (NDAs). These letters are like purgatory for NDAs — they’re not quite approved for consumer use, yet they’re not quite rejected.

Proof of the increase in the use of this device was substantiated thanks to the effort of Chris Milne of the Tufts Center for Drug Development. As of October 1st, 2007, 36 approvable letters had been issued by the FDA since January 2006. By comparison, 35 similar letters had been issued between 2001 and 2004.(1) The approvable vortex generally appears to put the drug into a suspended animation of sorts until certain issues can be resolved as outlined by the FDA in their response. While the prospect of being an approvable drug sounds encouraging, the reality is that the average time a drug remains approvable is 20 months, and drug makers must expend additional resources in order to bring the necessary evidence to the FDA for the drug to be approved. In some cases, as highlighted by the article, this will cause the drug company to throw out the NDA altogether, claiming the requested data would be impossible to retrieve in a timely fashion. Some examples cited:

• After the FDA issued an “approvable” letter for its diabetes drug, Pargluva (muraglitazar), Bristol-Myers Squibb ended up withdrawing the drug because it claimed it would take 5 years to gather the data requested in the letter.
• Sanofi-Aventis’ Acomplia, intended to fight obesity, got an approvable letter from the FDA in 2006 but then was given an unfavorable review from an FDA advisory committee in June this year prompting the French firm to withdraw its NDA. For more information on this, you can see the 2 articles I wrote about the drug here, before the FDA released its findings and here, after the FDA released its findings.
• The anticipated diabetes blockbuster for Novartis, Galvus (vildagliptin), received its US approvable letter in February 2007, but the additional clinical trials required by the FDA are anticipated to push its launch to 2009, putting it well behind its competition Merk and their drug, Januvia. The projected cost for the delay is $500 million in unmet projections.

There is a question as to whether these delays can be attributed to safety concerns, politics, or a little of both. The article indicates that the trend to send an approvable letter indicates that the FDA is raising the standard for drug safety, a sentiment supported by the fact that most of its letters ask for additional data regarding a specific “safety signal” or more general information around heart and liver toxicity. We can surmise this more conservative approach is probably due to pressure it’s receiving from congress to ensure another Vioxx scandal doesn’t ensue, yet they proclaim a desire to recapture their image of being a guardian of public health, unshackled by the burden of politics.

If I had to choose between one or the other, I would prefer an FDA that didn’t answer to lobbyists or politicians, and wasn’t under the pressure to approve blockbuster drugs without the benefit of time to truly study their effect on human subjects. I think most of the confusion stems from the fact that the FDA had no consistent leadership from about 2001 until last spring, when Andrew von Eschenbach was appointed to head up the organization. With his appointment and an in-depth examination of how the organization is run, I’m confident they can regain some of their luster as the custodian of the food and drug market in the US.

In examining the available data, the organization might not be as bad off as it may initially seem. As Tufts’ Chris Milne states in the article, “Withdrawals of Drugs happen in a cluster — every three to five years. But the actual rate of withdrawals is consistent over time at three percent.” Hence, the FDA doesn’t seem to be approving riskier drugs as a result of changes in the length of its approval process. What does need to be better communicated to the public, perhaps, is that there is a safety-to-benefit ratio that is considered for approval of a drug, and for each patient a drug’s advantages need to be weighed against its risks. Chances are that a change to a length in the approval process in order to appease political forces won’t change this safety-to-benefit ratio, and won’t prevent something like Vioxx from happening again.

I find all these demands for a change to the FDA approval process a little overzealous, and while I think a strong, lean organization is necessary to ensure drug safety for all, even the most efficient of organizations will make mistakes. We have a tendency to point fingers at a government agency to protect us in extreme scenarios, and when something unusual occurs we feel the need to “fix” the problem. We must make changes with the anticipation that we’ll never have a perfect organization because the needs of the public will demand change within even the most established organizations.

We saw an increase in the amount of time it takes for people to get through the airport after 9/11/2001 in the name of safety. We needed someone to make us feel like there was a watchdog, a guardian protecting our interest in the skies. Yet, news agencies continually report how mistakes are made at airports and publicized as a horrific collapse of the organization that is meant to protect us. Which do we want, better safety or a more convenient, quicker airport experience? Is the FDA destined for the same fate? Do we anticipate long, drawn-out approval processes for benign drugs while the occasional toxic drug will slip through the cracks? Must we reexamine the organization every time it will make a mistake in the future and have our politicians demand change and reorganization and simplification?

I don’t know what the answer to any of these questions is, but I do know that things seemed a lot simpler when I was younger and regulations didn’t seem to burden the every move of government agencies that were meant to protect us. We almost seem to want to create a scandal where none exists.

It seems to me that the FDA does need to invite change into its charter, but it needs to become a more lean organization. Its established process for drug approvals seems to be thorough enough, and you can see a basic flowchart of a standard approval process here. Perhaps what needs to be better established is what the FDA can do after a drug gets into a market, and establishing rules for Pharmaceutical companies to better communicate the risk-to-benefit ratio of their drugs to the doctors that prescribe them.

What are your thoughts? How well do you think the FDA works? Do you think it actually needs a change? Do you feel the FDA is largely responsible for the Vioxx issue, or is it more in the hands of its owner, Merk? Can you compare the agency to its counterparts in other countries? Do you feel we could learn a lesson from them?

I’d love to hear what you have to say! And please, I encourage you to check out the full article that I analyzed for this blog in this month’s issue of the Pharmaceutical Executive! You can get the full text of the article online here.

(1) See “FDA’s Approval Problem,” Walter Armstrong, Senior Editor, Pharmaceutical Executive, November 2007, pp 56-64, 118.

Naturally, when an article appears on the site that touts advances that Massachusetts is making in terms of the promotion of cleaner-burning fuel and more environmentally-friendly products, I pay particular attention to it. In fact, it happened to me a few days ago when the site reported that Massachusetts political leaders are proposing “first-in-the-nation mandates and incentives to promote the development and use of biofuels, with the hope of reducing the state’s carbon emissions and dependence on foreign oil.” (1)

The state’s plan will promote the use of biofuel in its economy in 2 ways. First, it would require that heating oil and diesel fuel to contain up to 5% of a biofuel derivative by 2013. Though current biofuel-based heating oil may cost the same or even slightly more than its petroleum-based counterparts, officials are hopeful that with prolific use the price advantage would eventually belong to the environmentally friendly fuel.

Some companies are already seeing success with blended heating fuels such as Mass Biofuel, a division of Fisher-Churchill Oil Company in Dedham. They indicate that 390 of their customers currently purchase either an 80-20 blend of regular heating oil mixed with biofuel or a 90-10 blend of low-sulfur heating oil mixed with biofuel. While the 90-10 mixture is slightly more expensive because of the low-sulfur content (about $0.10/gallon), the 80-20 blend is the same price as regular heating fuel, and each option is becoming increasingly popular with their customers. Ultimately, the price of blended biofuels is expected to reduce the cost of heating oil over time.

The second change in this plan would be an exemption of the state’s $0.23 gasoline tax from any ethanol gas produced from plant products other than corn. The intent is to provide incentive to gasoline dealers to carry the blended fuel and to Massachusetts-based manufacturers to produce it. Mascoma Corp., based in Cambridge, is already studying the viability of producing cellulosic ethanol, derived from vegetation such as wood chips, algae and grass, as a commercial product.

I am very excited by the prospect of these new fuels, and am particularly enthusiastic about the introduction of the cellulosic fuels in our gas pumps. With what seems to be an abundant supply of plant waste or easily renewable plant matter, we could not only potentially reduce our dependence on fossil-based fuels in the near future, but less harmful emissions would be produced in the environment as a result of the reduction in sulfur and other harmful chemicals burned in today’s conventional fuels. But in order for it to be effective, how fast would Massachusetts’ initiative have to be enacted? How quickly would it have to be adopted by other states in the union, or for that matter, other countries in the world? Granted, the U.S. is probably one of the biggest offenders now when it comes to pollution, but we’re not producing all of it.

In spite of the changes coming from Massachusetts, however, there are some drawbacks to be considered before we get too excited by this plan. I think this is a great first step, but there is still more work to be done. Heating and automobiles are only a small piece of the puzzle, we need to do more about energy production as well. As you may recall I had one person, Ginger, comment on my “Wonder Wheat” article, “Someday we’re just going to have to stop using so much of everything. Biofuels are, unfortunately, no solution. They just mask the problem for a little while.” Conservation will be every bit as important as we battle for the planet’s health. We need to become more cognizant of our wastefulness.

I’d be interested to hear about what you think of the article. Do you think these sorts of changes would be welcome in New Jersey, New York, Florida, or some other state? What about California, which has typically lead the nation with tough requirements for environmental friendliness, do you think they’ll be following shortly? What do you do currently to show your commitment to the environment? Share your thoughts, I’d love to hear them.

(1) See “New push for renewable energy,” Bruce Mohl, Boston.com, November 6th, 2007.

Well, according to a report I found on the Boston.com site entitled “Panel urges recall authority for FDA,” we may be witnessing history again. Recent recalls of dangerous toothpaste, toys and dog food prompted the creation of an advisory commission by the Bush administration to examine the incidents more closely and determine ways to better handle similar incidents in the future. As a result of their findings, the commission will advise to President Bush that the Food and Drug Administration be “empowered to order mandatory recalls of products deemed a risk to consumers.” (1)

The FDA has no such authority now, and the current process requires that the organization work with manufacturers on voluntary recalls. The agency currently depends on warnings and bad publicity for the offending company in order to get a product removed from the market. This kind of process, however, could take time, and the committee believes that threat of legal action and fines could prompt a quicker response from offending companies.

Complementary to the recommended changes to the FDA, the panel urges the increased presence of U.S. Inspectors at agencies responsible for products imported into the United States, such as the Customs office and the Border Patrol, and increased authority for the Consumer Product Safety Commission (CPSC). The changes to the CPSC are particularly far-reaching, allowing the agency to make it illegal for a firm to knowingly sell a recalled product, authorizing it to make follow-up recall announcements and requiring companies issuing a recall to report supplier and delivery information. The CPSC would have the legal authority to impose fines and other punishments for those companies that did not comply with the new recall guidelines.

According to the report, which you can read here, the reason for encouraging this increased authority is the staggering increase in imports into the United States since 2000. It claims that imports will triple by 2015 with increased demand from Americans of foreign products. The burden of these changes will require more scrutiny from import gatekeepers such as the CPSC, and more clout from the FDA if dangerous materials do make it to market.

When I first read this article, I believed the recommendations of the committee were a bit overzealous, and would increase the bureaucratic “red tape” required to bring good products to consumers. However, given the increased number of variables that imports may introduce that are beyond the FDA’s control, it may not be a bad idea to improve the structure of their authority. Clearly, under its current setup the FDA requires some changes to give it a better handle of the current market, and prevent the kinds of mistakes that have lead to big product recalls of both food and drug products in recent history. After all, I had just assumed the FDA had the ability to recall products; I did not know that only the manufacturers could do so.

Additionally, I’d be curious to know if the FDA’s recall authority is inclusive of both food and drug products, or if it’s just food products. In recent memory, recalls of Bextra, Vioxx, and children’s cough & cold medicines have all be voluntary, indicating to me that they may not have that authority. In the new system proposed by the advisory committee, would companies still be given the opportunity to recall their products first? To me, it’s more impressive if a company knowingly recalls its own products than if the FDA requires them to do so. The former indicates a concern for the company’s customers’ health, and an understanding of the legal ramifications of continued sale of their recalled products. I would likely still buy other products from that company, products proven to be safe. The latter scenario would project a company unwilling to take responsibility for its actions, such that it needs to be told what to do, like a parent to a child. It would be enough for me to cease buying any products from that company.

How do you feel about this? How would an FDA-mandated recall change your opinion of a company? Should companies be given the opportunity to recall dangerous items on their own? How long do you give the companies before the FDA should step in? 24 hours? 8 hours? As always, your thoughts are welcome.

(1) See “Panel urges recall authority for FDA,” by Terrence Hunt, AP White House Correspondent, published on Boston.com, November 5, 2007.

But she never got the medicine. Because of the US Food and Drug Administration’s (FDA’s) requirements to test both the safety and efficacy of the medication, and the lengthy clinical trial process that follows, Abigail succumbed to her cancer in 2001. The experimental drugs that had been identified as potentially helpful did end up being approved between 2003 and 2004 and are used to treat cancer today.

The article does a good job of summarizing the issue currently in debate now at the FDA: should experimental drugs be made more readily available to patients for whom they may help, or should the gold standard of testing safety and efficacy dictate the course by which patients are allowed to test the drug? I was given some unique insight into this when I further researched a couple of historical events highlighted by the article: the first is the Food, Drug and Cosmetics act of 1938 that deemed it necessary to prove a drug’s safety before it could be sold in the United States, and the second is the Kefauver Harris Amendment of 1962, which set up the framework for modern clinical trials and required that drugs be tested for safety and efficacy.

In 1937 and for several years prior, the drug sulfanilamide was widely used by doctors to treat streptococcal infections in both a pill and powder form. In June of that year, a pharmaceutical salesman for the S.E. Massengill Company in Bristol, Tennessee, had indicated that there was heavy demand for the drug in liquid form in southern states, presumably to dose children more easily. Up for the challenge, the company’s lead chemist and pharmacist, Harold Cole Watkins, developed a formulation using diethylene glycol into which the sulfanilamide would easily dissolve. The mixture was tested for flavor, appearance and fragrance before it was mass produced and shipped all over the country.

The shipments were headed for their destinations, but one critical characteristic that the company had neglected to test was the compound’s toxicity. Pharmacological studies had not been done and Watkins’ failure to test it would lead to disaster. Diethylene glycol is a deadly poison, something used in certain formulations of antifreeze. Interestingly, lack of this test was not an illegal move at the time. The US did not require a drug be proven safe; it was simply assumed that a company wouldn’t risk bad business by sending out a drug that was unhealthy.

Well, this drug was most certainly not safe. The American Medical Association (AMA) started receiving reports in October that the drug had been used in several cases, and there was a high incidence of death and extreme pain in the patients taking the medication. Upon confirmation of the reports, the FDA dispatched a significant number of inspectors to track down and recover every trace of the drug that had been distributed by unwitting doctors. Though most of it was recovered shortly after the first reports were made available, over 100 patients died from poisoning. In one letter sent to then-president Franklin D. Roosevelt, one woman said:

“The first time I ever had occasion to call in a doctor for [Joan] and she was given Elixir of Sulfanilamide. All that is left to us is the caring for her little grave. Even the memory of her is mixed with sorrow for we can see her little body tossing to and fro and hear that little voice screaming with pain and it seems as though it would drive me insane. … It is my plea that you will take steps to prevent such sales of drugs that will take little lives and leave such suffering behind and such a bleak outlook on the future as I have tonight.” (1)

Because no laws existed preventing the sale of toxic substances, no legal action was ever taken against the company for its negligence in reviewing the toxic substance it had used in its drug. The only reason the FDA was able to seize distributed doses of the drug was because it had been mislabeled an “Elixir,” which by the FDA’s official definition, required an alcoholic component in its formulation. Without this mistake, the FDA would have had no legal recourse and it would have likely lead to more deaths as a result of poisoning.

This incident lead to the passage of the aforementioned 1938 Federal Food, Drug, and Cosmetic Act, which contained an added section covering new drugs to be sold in the United States. It outlined a drug testing protocol to provide better protection for the general public and was intended to prevent such a tragedy from occurring again. You can get the full FDA article here.

The new system was put a difficult test in 1961 when a Cincinnati, Ohio company named Richardson-Merrell attempted to bring a new drug, called thalidomide, to the United States from the German company that created it, Chemie Grünenthal at Stolberg. The company had synthesized the compound in 1953 while searching for an inexpensive method for manufacturing antibiotics from peptides. The drug was a failure at the original intent; it showed no appreciable effect as an antibiotic. In tests on animals, however, it showed no ill effect even at high doses. On that basis alone, the company decided that the best use for this new compound was to market it as a nonlethal sedative, even though no such effect had ever been observed in its studies on animals.

In a step to begin popularizing the drug, the company distributed free samples to doctors in Switzerland and Germany in 1955, and it was promoted as a treatment for seizures in patients with epilepsy. Though patients did not report improvement in the frequency of their seizures, they did report having a deeper sleep at night and a calmer mood during the day. The anecdotal evidence lead to Grünenthal performing experiments on mice to test its validity, and though the documented results were questionable, they were accepted by most European authorities. The drug was prescribed across the continent as a “safe” sedative, and it quickly became the drug of choice for helping pregnant women with morning sickness.

By 1960, Grünenthal enjoyed success with its drug throughout the world, but the United States was still an untapped market. As the sales team at Richardson-Merrell began preparing their documents for submission to the FDA, Frances Oldham Kelsey joined the agency and would be assigned as the agent responsible for reviewing the drug’s documentation and providing approval for the drug in the US market. The case was not expected to be lengthy or controversial. In advance of its approval, the FDA rules established by the 1938 Food, Drug and Cosmetic Act allowed Richardson-Merrell to distribute the drug on an “investigational” or “experimental” basis, which it did.

Kelsey, however, would prove to be the drug’s downfall. She was specifically interested in the fetal safety of the drug because she had studied quinine in the 1940s and its effects on pregnant women as part of a team of researchers trying to discover a synthetic cure for malaria. In one revealing study done on rabbits, she discovered that the substance was metabolized differently by pregnant rabbits versus their non-pregnant counterparts, and not metabolized at all by the embryos. She suspected that thalidomide may act in the same way, and therefore could cause serious side effects to the embryos of pregnant women, the very women who were taking the drug for their morning sickness in other countries.

Kelsey was additionally concerned that there was no acceptable “proof” that the drug behaved as a sedative; she needed to understand more about how the drug worked in humans. Several studies had been bypassed that might have shown the level of the drug’s toxicity over time, its effects on human metabolism, and its absorption rate, and a lack of manufacturing controls could not satisfactorily ensure the quality of the final product. Despite pressure from the Richardson-Merrell sales and marketing team to approve the drug, Kelsey refused the drug’s application 6 times over the second half of 1960.

In December 1960, the first reports emerged from Europe indicating there were possible toxicity effects from use of thalidomide among pregnant women. A most stunning letter published in the German paper “Welt am Sonntag” on November 18, 1961 by the German pediatrician Widukind Lenz. According to the letter:

Lenz described more than 150 infants with malformations, including phocomelia, and associated them with thalidomide given to their mothers. A stunning statistic was that 50 percent of the mothers with deformed children had taken thalidomide during the first trimester of pregnancy. The limits of danger were amazingly narrow: women who took even one tablet of thalidomide between the 20th and 36th day after conception were at risk for delivering malformed infants – beyond that time, the drug caused no deformities at all. (2)

The negative publicity eventually caused Chemie Grünenthal to withdraw the drug from most markets, and inform Richardson-Merrell of its decision. Kelsey’s persistence paid off, and most of the US public was spared from the side effects brought on by taking thalidomide, however, those pregnant women who participated in the “experimental” or “investigational” use of the drug suffered, so the rules needed to be changed.

In 1962, the Kefauver Harris Amendment was passed and gave the FDA better control over the experimentation of new drug substances on humans, and forced drug companies to prove both safety and efficacy of drugs. It lead to the birth of the 4-phase clinical trial structure that we enjoy today, and proves to be a more effective method in keeping potentially devastating drugs out of the market. You can read more about the fascinating history of thalidomide here, on Wikipedia (it is, incidentally, approved for use in the US today, though certainly not for the same effects for which it was advertised back in the 1950s and 1960s).

So, two major incidents in our drug history brings us to where we are today (with some other changes over time, of course). The clinical trial framework has been arguably the most beneficial development for keeping unsafe and ineffective drugs off of our drugstore shelves. However, one can see how it can be a hindrance to those whose life is threatened and who may not have many alternatives that will result in living longer. Should our structure be changed? Is the lengthy period associated with approvals a detriment to someone who might only have a few weeks, or even days, to contemplate their next steps? Do we release experimental drugs for use by terminally ill patients? What about people in perpetual pain? Where do we draw the line?

Please, share your thoughts!

(1) See “Taste of Raspberries, Taste of Death: The 1937 Elixir Sulfanilamide Incident,” written by Carol Ballentine for the June 1981 issue of the FDA Consumer Magazine.

(2) See “Thalidomide,” written collaboratively in Wikipedia

Dr. Rosen sat on the FDA panel that recommended that the new warning label should be issued, and it seems his participation was a catalyst for his deeper analysis of the process that brings these drugs to market. What Dr. Rosen claims is at issue is the methodology the FDA employs in testing medications for public use. Currently, clinical trials are set up to test a medicine’s efficacy against the disease or affliction it’s intended to treat, but there is no study as to whether the drug increases lifespan or improves quality of life. Such an effort would require substantially longer clinical trials, sometimes taking years to complete, but Dr. Rosen claims that by making this effort patients would benefit from the better understanding of the long-term effects of the drug.

Dr. Robert Temple, who is one of the top clinical trial designers for the FDA, argues against Dr. Rosen’s approach because he claims it could have the unintended consequence of slowing the approval process and increasing the cost for life-saving drugs. The push for speedy approvals came in the early 1990s, during attempts to get HIV and cancer treatments to patients more quickly, and the agency asserted that it was willing to pull drugs from the market if the early predictions ascertained from the trials proved wrong.

But the FDA may not have much of a choice in the matter. Today’s Boston Globe reports that incidences of drug reactions nearly tripled between 1998 and 2005, further evidence that the FDA’s current methodology for reviewing drug safety isn’t working and needs some evaluation. Thomas Moore and Michael Cohen of the Institute for Safe Medication Practices, a nonprofit educational group that analyzes drug safety issues, published their findings in the Archives of Internal Medicine. They say that the number of deaths and serious side effects from 1998 to 2005 grew from 34,966 to 89,842.

Conditional approval of drugs could be one way that the FDA could avoid controversy and keep current practices in place, says Harvard Medical School professor of medicine Dr. Jerry Avorn. If the speedier tests prove the drugs effective for treatment of an ailment, then they could be released on that criteria alone. At regular intervals, the FDA could analyze statistical data on a new drug to ensure that its proposed overall effect, an improvement in the quality of life, was the true result of its use. In absence of this proof, the drug would be pulled from the market. In this way, no delays to get drugs to market are necessary, and life-saving drugs are delivered to those who need them.

Which is the right move? Would it be better to create a more thorough, if laborious and costly process to get a broader picture of a drugs effects on a patient’s life and overall health? Would better tracking of patients living with the treatment give a better understanding of the effects and appropriate actions for drugs that might be dangerous? Or do you feel that the current system works fine the way it is, and doesn’t require any kind of serious change?

I would contend that the current system is broken, and a hybrid of the ideas above is necessary. If people are dying, drugs that could help aren’t likely to make them any worse off. Obviously, the choice is ultimately the patient’s, but I believe the wise choice would be to continue to bring oncology and HIV treatments to market more quickly. Drugs that deal with pain are a little more difficult. In reality, pain shouldn’t kill you, but to live with it every day is not something I’d wish even on an enemy. Other drugs should probably have the highest level of scrutiny, because it’s possible the cure is worse than the disease.

What do you think?

Merck & Co., based in Whitehouse Station, has been especially visible during this turbulent time, one of the first to receive heavy public criticism for their handling of the information about Vioxx and its dangers to people using the anti-inflammatory CO2 inhibitor. The Vioxx Defense fund, created to pay for the legal defense of its drugs, is about $810 million, and was likely much more at the start of its defense.

Merck saw a victory today in its case, in which the Supreme Court of New Jersey ruled that a nationwide class action law suit, similar to that which was taken against tobacco companies in the last decade, is inappropriate for this case. Class action law suits are intended to minimize the legal burden of hearing multiple cases on the same issue and compounding all cases into a single suit. While this type of action has many advantages because it brings to light those people who may have been underrepresented by their own law suit, its critics claim that the action dilutes the rewards to those who need it and gives benefits to those who don’t. Wikipedia has an extensive article on class actions here.

The work for Merck is not done yet, however. They are still likely to fight several individual law suits over the course of the next few years (27,000 are still pending), which claim that Vioxx is the cause of unexpected heart attacks or strokes. However, even in that cloud there is a silver lining for Merck, as more than 1170 of those cases have been dismissed, and even those that have gone to trial have favored the pharmaceutical company; Merck has won nine and lost five. The Boston Globe ran an excellent article summarizing the details of the dismissal, and you can read greater detail on this and other information in the trial here.

Don’t misunderstand me; I am no apologist for the failings of Merck in this Vioxx case. I certainly believe they failed to properly inform their customers of the risks of this medicine, and they deserve more than a slap on the wrist as penance. However, there are more agencies at work here, government agencies such as the FDA that are supposed to protect us from the mistakes these pharmaceutical companies can make. Was Vioxx rushed to market without appropriate analysis of the clinical trials that were conducted? And for the tens of thousands of people this drug was helping, had they been aware of the risks of the drug would they have continued taking it? What is acceptable risk in medicine, and who gets to decide?

All drug companies have a place, and unlike tobacco that provided a recreational drug that was known to be dangerous, class action lawsuits threaten the good that these companies do for society. Oncology drugs, other pain medications, and diabetes treatments, just to name a few, often give people back a quality of life that they might not otherwise have had. Drug companies should be better regulated and certainly punished when they knowingly dismiss those regulations, but creating scenarios that could run them out of business would not be beneficial to any of us.

What are your thoughts?