Michelle Hoffman, editorial director of Pharmaceutical Technology.

Michelle Hoffman

I was hanging out with a friend this weekend, when we got on the subject of drug advertisements on TV. My friend started imitating the way people are pictured in those ads frolicking through a beautiful garden or gamboling in a fairy-tale woodland while all of the awful side effects of the drug are being read quickly in the background. Is it any wonder, we remarked, that people don't take seriously enough the potential risks of taking any drug? 

Interestingly, I'd had almost the exact conversation with a work colleague the week before. He was considering the issue of how to communicate risk to the public and wondering why the public gave too little heed to the potential side effects of a new drug they had available to them.  

On the other hand, he pointed out, some people wouldn't even visit a doctor to inquire about a particular medical condition if those drug ads hadn't made them aware of both the condition and the fact that a potential treatment were available for it.  

So which is it? Do drug ads provide a public service, or do they serve only to boost awareness of a drug product without any concomitant awareness of the risk of taking that drug? 

Rooting around the Internet, I discovered that in 2002, the US Food and Drug Administration surveyed patients and physicians to determine the impact of direct-to-consumer (DTC) advertising on consumer (that is, patient) behavior. Even though the survey was performed a while ago, its findings are relevant to the discussions I've been having. Forty-three percent of patients responding to the survey were prompted to seek additional information about the drug described in the advertisement, and over 60% of those sought information about side effects from healthcare providers, pharmacists, and on the Internet.  

While more than half (58%) of the patients believed the ads provided enough information for them to decide whether to discuss the drug with a healthcare provider, an even greater number felt the ads adequately stated the drug's risk. A smaller percentage (44%) of respondents thought the ads did a poor job of enumerating the drug's benefits.  

Almost the same percentage of physicians (41%) felt their patients were confused about a drug's benefit because of the DTC advertisement. Approximately 40% of physicians also felt  their patients did not understand the risks and possible negative effects of the drugs.  

The FDA report concluded that DTC advertising was good to the degree that it motivated patients to think more about their health and to find out more about treatments available to them. They also found it "troubling" that the advertisements "overstate drug efficacy and do not present a fair balance of benefit and risk information." 

In an earlier editorial, I suggested that drug makers hold off on DTC advertisements for a few years after the drug has launched until its risks are better known. It is also clear that these risks need to be enumerated more clearly and not obscured behind images of frolicking, happy people.  

If that happens, it may be possible that DTC advertisements will be more public service and less self-serving.

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Articles

The good, the bad, and the ugly about direct-to-consumer advertising.

Public Service Versus Self-Service

Anyone who lived through the '60s and remembers it undoubtedly had some experience—direct or otherwise—of tetrahydrocannabinol, the active ingredient in marijuana. The drug produces what many consider to be pleasant effects on the nervous system, the likely reason for its popularity. And that led to two general conclusions. The first was that the drug mimicked some chemicals that could be made and found within the human body, and second, that these endogenous cannabinoids would most likely be found in the brain. 

After many years of research, scientists are in fact uncovering signaling systems that operate 

 cannabinoid messenger molecules. But much to their surprise, the collection of receptors and endogenous cannabinoids (endocannabinoids) are found more diffusely throughout the body. 

, Vincenzo Di Marzo, a member of the  Endocannabinoid Research Group at the Institute of Biomolecular Chemistry, National Research Council in Naples, Italy, recounts the number of pathologies in which endocannabinoids have been associated and, presumably in which cannabinoids may offer some therapeutic benefits. These include pain and inflammation, immunological (autoimmune and allergic) disorders, neurological and neuropsychiatric conditions, obesity, metabolic, and cardiovascular disorders, cancer, and disorders of the gastrointestinal track as well as the liver.  

The diversity of physiological systems and conditions regulated by endocannabinoids opens up a tremendous number of potential novel therapeutic interventions for a variety of diseases. At the same time, it opens up the possibility that each cannabinoid-based therapeutic will have a tremendous number of side effects.  

In conclusion, says the author, "for those who are engaged in developing new therapeutics by targeting the endocannabinoid system, this task can be described by Giuseppe Verdi's definition (in La Traviata) of love as 'Croce e Delizia': a series of painstaking, and sometimes frustrating, efforts alternating with immense gratifications."

Source: V. Di Marzo, "Targeting the Endocannabinoid System: To Enhance or Reduce?" 

Scientists are uncovering signaling systems that operate via cannabinoid messenger molecules.

Coming Down the Pike: Endocannabinoids

Several articles that appeared in early April in the scientific press signaled the end of a research era of sorts, if they didn't constitute a downright obituary for it. After more than 20 years of searching, the AIDS research community is raising something of a white flag on the search for a prophylactic vaccine. They didn't quite say it that way, and they're not really giving up, but following the failure last fall of a clinical trial conducted by Merck &Co. (Whitehouse Station, NJ) on a vaccine for which the community held high hopes, leading AIDS scientists are urging their colleagues to go back to the drawing board. That is, they're calling for the community to spend less money on product development and more on basic research. 

Of course, researchers have worked for a long time on other disease conditions—cancer comes most readily to mind—and have not produced a prophylactic vaccine or a cure. The difference is that cancer is a term that applies to any number of diseases, which affect many different organs and cell types. In addition, many endogenous and/or environmental factors contribute to cancer's onset and progression. HIV, on the other hand, is the only agent that causes AIDS. It has a finite number of genes and proteins, most of which have been studied in exquisite detail since the virus was first linked to the disease about 25 years ago. So, I'm wondering what researchers expect to find when they go back to basic research that they haven't found before? 

In spite of this seeming impasse, I have to remark on the incredible creativity that has gone into AIDS research. Scientists tried strategies that, although they did not work with AIDS, will and have undoubtedly advanced vaccine protocols for other diseases. AIDS research also accelerated the pace of molecular biological development beyond what it might otherwise have been in less urgent circumstances.  

Nevertheless, HIV is a formidable and slippery foe, slippery because of what seems an almost dastardly ability to mutate to resist or elude any prophylactic trap set for it. 

In an editorial appearing in the April 3, 2008, issue of 

, the journal's editor writes that the AIDS vaccine "crisis" is one of the field's own making. The AIDS vaccine research community has fairly consistently made promises it could not keep. The 

 editorial cautions that other disciplines are also susceptible to hype and oversell, offering the examples of stem-cell research, Parkinson's disease, and autism. To that list I would add gene therapy and siRNA (small interfering RNA).  

I agree that many of these technologies get pushed prematurely into the clinic and then wither because of both waning scientific interest and investment interest. But I would offer an additional lesson from the AIDS vaccine situation: Beware of anyone who claims that a new biotechnology is going to produce an imminent cure. These technologies are powerful and will someday produce fabulous benefits, but probably not immediately. Those in the investment community need to likewise learn the value of long-term investing. Forcing promising technologies into the clinic too early almost always dooms them—at least temporarily. Remember that monoclonal antibodies are only now realizing the promise they held some 30 years after they were developed. 

There's one more lesson to learn from the so-called AIDS vaccine crisis. In an article in the April 4, 2008, issue of 

, the AIDS research community acknowledged that the 

 monkey model now used to test potential vaccines isn't working well and agreed that they need to find a more predictive animal model. That makes a lot of sense. Having the right animal model, it seems to me, is key to finding effective therapies for just about everything. The question I have is that after using this model for about 20 years, why are they just now questioning its validity? 

The good news with AIDS is, as it's always been, that the vast majority of cases can be prevented by human caution and vigilance. That's also the bad news.  

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Scientists are giving up on a preventive vaccine for AIDS, but there are lessons to be learned.

Requiem for a Vaccine

As we went to press, a memo written by John Jenkins, director of the Office of New Drugs (OND) at the US Food and Drug Administration, came over the transom. I think it speaks for itself. I will simply add, once again, that as we enter this presidential election season, we must demand that our aspiring presidents recognize that the "healthcare issue" involves more than just who will pay for consumers' use of prescription drugs, but also how we make and approve those drugs. Here, in its entirety, is Jenkins' memo: 

"Over the past several years, the rate of growth in workload for OND has far outpaced our ability to increase our staffing. The workload growth has occurred in many areas, including the number of meetings conducted with sponsors, the number of requests for Special Protocol Assessments (SPA), work related to emerging safety issues and early communication, work related to responses to Congressional inquiries, etc. This workload imbalance was one of FDA's primary areas of focus when we were discussing with industry the PDUFA II and PDUFA IV program, and the PDUFA IV program includes a significant increase in resources to FDA to help address the workload concerns through increased staffing and better IT systems. 

"More recently, we are faced with the increased workload related to the implementation of FDAAA (FDA Amendments Act) and FDA's Safety First/Safe Use initiative. In addition to the resource increases under PDUFA IV, FDA also saw increased appropriations for FY 2008 to help meet the growing workload. The new resources will have a significant impact on our workload-staffing balance in the long term, however, in the short term, CDER is approximately 550 FTEs below its ceiling for FY 2008. 

"While we are working hard to recruit and train the necessary new staff (including replacement of staff who depart CDER for various reasons), it will take several years to achieve full staffing and to have all the new staff fully trained and productive. In that interim, it will be necessary for CDER and OND to make careful decisions about our work priorities, and those priorities will be reflective of our stated goals under Safety First/Safe Use to ensure proper balance between our focus on preapproval activities and postapproval safety issues.

"To that end, I have granted permission to OND division and office directors to make decisions to bring their unit's workload into better balance with their existing resources. These decisions will be made on a case-by-case basis since the balance is not the same in all divisions or even the same over time in any given division. We will still strive to meet our PDUFA goals whenever we can, however, in some cases we may not be able to meet PDUFA goals and managers have been given the discretion to make those decisions. We have actually failed to meet many PDUFA goals (e.g., goals related to meetings with sponsors) over the past few years, although we have generally been able to meet most of our application review goals. In the short term, our ability to meet PDUFA goals is expected to decrease. In some cases we may have to cut back on work by declining requests from sponsors for guidance (e.g., meetings, multiple cycle SPA reviews) and in other cases we may decide to go past the PDUFA goal date for review of an application. In cases where we decide to go past the PDUFA goal date the sponsor will be notified by the division management of that plan.

"It is important to note that decisions to miss the PDUFA goal date are separate and distinct from a decision to extend the PDUFA goal date by three months, which is allowed in response to the submission of a major amendment during the last three months of the review cycle. 

"CDER faces significant challenges in hiring the 550 additional staff (plus replacements for staff who depart for various reasons) authorized in our budget for FY 2008. First, we have to find qualified candidates for the positions. We are aggressively undertaking that part of the effort through various channels including extensive advertisements and the use of recruitment incentives. Once we have identified a qualified candidate they must navigate through the complex Federal/HHS personnel system before they can receive an official job offer. We have worked to gain permission to streamline that process as much as possible, however, in many cases it can still take months for the paperwork to make its way through the system before an official job offer is made. In some cases, candidates choose to take other positions before an official job offer from FDA can be made.

"Finally, our pay structure often is not competitive to what qualified candidates can make in the private sector. We are working through existing authorities to make FDA's pay as competitive as possible.... As noted above, it is likely to take several years before CDER achieves full staffing and all the new employees are fully trained and productive. It can take 1–2 years, or more, for a new reviewer or project manager to be trained to do the complex work required at FDA. We will be continuously assessing our workload and resources over time and make decisions on our priorities. There is no specific end date since I cannot predict when our resources will be in balance with our work. That is why there is no blanket policy but rather permission to reduce work as needed on a case-by-case basis."

Send your ideas and comments to Editor-in-Chief 

The FDA itself issues a cry for help. Is anybody listening?

Message in a Bottle

Antibodies are highly specific molecules that can be tailored to recognize almost any stretch of peptide that nature can conjure: a feature that has been exploited for years now to produce therapeutic antibodies.  

BiTE antibodies may be able to fight cancer cells such as this one.(PHOTO: GEOSTOCK/GETTY IMAGES) 

    In the most common scenario, an antibody is created that homes in on a particular protein—generally one abnormally expressed to produce a disease condition—binds to it, and blocks its activity. The anti-breast cancer drug Herceptin functions this way, for example. 

    But within the past 10 years, scientists have been experimenting with antibodies that recognize two peptide sequences—often on two different cell types—at once. These so-called bispecific monoclonal antibodies (Bi-mAbs) are often engineered to recognize a sequence on cytotoxic, or "killer" T-cells as well as a sequence on tumor cells, the idea being that the Bi-mAb literally links together a killer cell with its tumor-cell target.  

, scientists at Micromet Inc. (Bethesda, MD) say that most of these drugs have not been "suitable for formal pharmaceutical development, generally due to issues of production and lack of potency." And speaking at the Biotechnology Industry's Organization CEO and Investors Conference this February, Micromet CEO Christian Itin revealed the company's next-generation Bi-mAbs, which they call BiTE antibodies.  

    BiTE antibodies combine only the variable domains of antibodies and therefore are approximately one-third the size of conventional antibodies. Scientists report that BiTE antibodies have been extremely successful at inducing the normal "killer" T-cell response in a highly specific manner against tumor cells, while skirting many of the usual side effects of mAb therapies. The company has its first such BiTE antibody in Phase I trials for non-Hodgkins lymphoma and has several more against various tumor types in its development pipeline. 

1. P. A. Baeuerle et al., "BiTE: A New Class of Antibodies that Recruit T-Cells," 

2. C. Renner et al.," Cure of Xenografted Human Tumors by Sispecific Monoclonal Antibodies and Human T Cells," 

3. M. Brennan et al., "Preparation of Bispecific Antibodies by Chemical Recombination of Monoclonal Immunoglobulin G1 Fragments," 

Antibodies are highly specific molecules that can be tailored to recognize almost any stretch of peptide that nature can conjure: a feature that has been exploited for years now to produce therapeutic antibodies.

Coming Down the Pike: Bispecific mABs

Finally, after years of focusing almost exclusively on kinases as targets for anticancer therapies, a new class of compound makes the jump from research laboratory to clinical development. The new kid on the block: Histone deactelyase inhibitors (HDAC inhibitors). These compounds prevent the expression of cancer-inducing genes by maintaining them in a suppressed state. Essentially, these new potential anticancer therapies take advantage of an epigenetic mechanism of controlling gene expression. That is, certain chemical modifications can suppress the expression of genes without altering the intrinsic sequence of nucleotides in the DNA code—hence the notion of epigenetic modification. Instead, these modifications—chiefly methylation or  acetylation—somehow alter the structure of the chromatin in which the gene lies in such a way that a particular stretch of chromatin is tightly coiled and resistant to unwinding by transcription factors that might otherwise stimulate gene expression. If the suppressed gene contributes to carcinogenesis, then inhibiting its expression should inhibit its ability to cause cancer. HDAC inhibitors function by preventing the removal of suppressive acetyl groups from histone proteins on the chromatin.  Several large pharma and biotech companies are developing HDAC inhibitors as anticancer therapies, some of which are in clinical trials.  

M. Paris et. al.,  "Histone Deacetylase Inhibitors: From Bench to Clinic,"

, ASAP Article, 10.1021/jm7011408, (Feb. 5, 2008), available at 

pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/asap/abs/jm7011408.html