Presented to the
International Low Vision Support Group
by Dan Roberts
[Opening: montage of screen shots and audio of disclaimers from drug commercials]
Pretty scary, isn’t it? Kind of like telling us we’re going to feel better or die trying.
These commercials, which show peaceful scenes of happy people while a disembodied voice warns us of impending doom, are a sometimes absurd outcome of an important issue: drug side effects. While the company wants us to ask our doctor about the latest miracle cure, it still must satisfy strict government regulations in the testing and marketing of its product. And one of those regulations is that the public must be told about every possible adverse event that may accompany it.
This doesn’t mean, of course, that we are going to be affected by all of those side effects. It just means that during the testing phase of the drug involving thousands of people, at least one person got dizzy, or felt nauseous, or even passed away. All of the unexpected events have to be reported, and–because it’s required by law–we get to hear them listed. At least the advertiser shows us nice pictures and plays pretty music to take our minds off of the disasters that might befall us.
Drugs can affect different people in different ways. In addition to acting upon a disease, a drug can cause other conditions called side effects and adverse events. Some side effects are minor, while others can be dangerous. Some affect a large percentage of people, while others affect only a few. These factors have to be weighed against the effectiveness of the drug to determine if it should be approved for the market. The first phase of a clinical trial, the “safety and efficacy” phase, is designed to study two things: whether the drug works for a significant majority, and to identify any potentially serious adverse events.
No approved drug is without side effects. We trust, however, that they are few and acceptable. You may develop a temporary headache, or you may experience nausea. Or you may have no adverse reactions at all, and that is supposed to be the majority case. Before any drug treatment is administered, the doctor should advise you of all side effects that showed up in the trials. You will then be asked to sign a consent form to verify understanding and to give approval for the treatment. This is called “informed consent,” and it is required in every case. The consent form should be read thoroughly by you or your representative, and any questions should be answered ahead of signing.
So how safe are we? If the percentage of adverse events during clinical trials is too concerning, the FDA will not approve a drug. For that matter, if the risk appears too great, or if the trial design does not pass scrutiny, approval may not even be given to take the drug into trials in the first place. This is the system that protects us from snake oil salesmen. It isn’t perfect, and it isn’t always foolproof, but it’s the best we have at this time.
In addition to government regulation, responsible drug use can also reduce our risk of harm from adverse events. This means more careful and precise administration of the drugs and close monitoring of our ongoing physical response to them.
The term “side effect” is similar to the term “adverse effect”, but the two should not be confused. Side effects can be either beneficial or harmful, whereas adverse events are always harmful, with undesired complications secondary to the intended effect of the drug.
Adverse events can lead to worsening of the disease, mortality, changes in body weight and levels of enzymes, loss of function, pathological changes at the microscopic, macroscopic or physiological level, changes in susceptibility to other chemicals, foods, procedures, and negative interactions with other drugs. Generally, any event which causes death, permanent damage, birth defects, or requires hospitalization is considered a serious adverse event (SAE). If SAEs are found in drug trials, they are required in many countries to be reported in the research and listed in the labeling of the medication. In the United States, MedWatch is the main reporting center, operated by the Food and Drug Administration (FDA). Similar agencies exist in other countries, as well. These include the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, the Australian Drug Evaluation Committee (ADEC) in Australia, the Centre for Adverse Reactions Monitoring (CARM) in New Zealand, the European Medicines Agency (EMA) in the European Union, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, and Health Canada in Canada.
Drug safety is a major concern of the public and drug manufacturers. The government, therefore, has become increasingly more involved in regulation. The days are gone when a salesman could pull into town and sell medicine out of the back of a wagon, with nothing to back up his claims other than the shill in the audience who was paid to be miraculously cured before our eyes.
Today, agencies such as the FDA are responsible not only for approving drugs but also for monitoring their safety after they reach the market. Timely and accurate reporting of adverse events by pharmaceuticals and physicians is important, especially in the case of newly marketed drugs. Physicians are expected to report to the pharmaceuticals, and the pharmaceuticals are expected to take appropriate action. This could mean anything from simply notifying physicians of potential risks to withdrawing the drug from the market.
Unfortunately, unreported serious adverse events are still too common. And unreported cases of severe adverse events resulting from poorly designed clinical trials can lead to public health disasters. Well-known examples are the fen-phen and thalidomide episodes. Fen-phen, a weight loss drug, was discovered to cause valvular heart disease, and it was pulled from the market in 1997. Thalidomide was a sedative that was withdrawn from shelves in the late 1950s after causing numerous and severe birth defects. It was that particular tragedy that led to development of much stricter testing of drugs. Most drugs are associated with many nonsevere or mild adverse events, which do not affect every patient. But better reporting of more serious events is obviously necessary.
A good example of how the reporting process works is an action taken by Genentech Pharmaceuticals, after approval of Lucentis for treatment of the wet form of macular degeneration. The incidence of blood clots in the trial subjects was found to be 2.6% (19 of 721) in two combined groups of treated patients compared with 2.9% (10 of 344) in non-treated patients. The number of patients affected by the drug was not unusual for an older age group, and the difference between the treated and non-treated groups was not significant enough to block the drug’s approval in 2006.
Then, about five months after approval and clinical use, Genentech found that the higher of two recommended doses of Lucentis posed a 1.2% higher risk of stroke than the lower dose. The small risk of stroke from the treatment still did not pose a significant hazard to patients, but the company immediately sent notices to physicians to make them aware of the new data. This is an example of responsible reporting by a pharmaceutical company and physicians who properly comply with the regulations.
If the risk in this case had been high enough to pose a serious threat to the public, the FDA could have restricted distribution of the drug or even requested that it be withdrawn from the market. The manufacturer could also have been given the opportunity to voluntarily withdraw the drug of its own volition. If the drug had then been removed from public use, the FDA would have announced it in a press release or a public health advisory. It may also have disseminated the information on its website, through articles in professional journals, and/or by way of presentations at scientific forums.
Some examples of adverse events from medications for eye treatment are:
- Glaucoma, associated with corticosteroid-based eye drops
- Central serous retinopathy, associated with corticosteroid injection
- Cataracts, associated with triamcinolone (Kenalog) injection
- Elevated eye pressure from anti-VEGF injections
Information about ocular side effects from non-ophthalmic drugs may be found at www.mdsupport.org/library/effects.html.
Drugs used in surgical and diagnostic procedures can also have adverse events on the eyes. Two common examples are:
- Temporary burning from betadine antiseptic solution (see www.mdsupport.org/library/betadine.html)
- Temporary stinging and blurred vision from mydriatics used for dilating the pupils
Prescribing information for approved drugs is always published for reading by physicians. The document includes a description of the purpose and pharmacology of the drug, instructions for dosage and administration of the drug, a description of the design and results of the clinical trial, information about who should not receive the drug. It also provides complete listings of warnings, precautions, and adverse reactions, and that is the part we hear in the commercials. Without an understanding of the research process, we could be overwhelmed, and even frightened, by the number of ways the drug could harm us. So let’s take a look at that part of a typical report.
The document used in this example is prescribing information for Lucentis, mentioned earlier. The first table lists and compares adverse ocular reactions affecting treated and untreated patients who presented with diabetic macular edema, age-related macular degeneration, and retinal vein occlusion.
Twenty-two adverse reactions affecting the eye are listed. These are conditions that affected the subjects during the trial period. Whether or not the conditions were caused by the drug treatment, they had to be reported.
Column 2, for example, compares two groups of 379 macular degeneration subjects each. Row 11 reveals that 3% of the treated subjects and 2% of the untreated subjects suffered from an inflammatory condition of the eyelids called blepharitis. The 1% difference in the groups was scientifically insignificant, and the percentage of people affected was small. The condition could have been caused by the drug treatment, but it could just as well have been a result of wearing old makeup. Still, it had to be reported.
On the other hand, row 4 shows that 24% of treated subjects experienced an increase in eye pressure, compared to 7% of untreated subjects. This was a significant difference and a safety concern, so monitoring of eye pressure became an important part of the treatment protocol.
Table 2 lists adverse events affecting parts of the subjects’ bodies other than the eye. 21 conditions were reported during the two year study that had occurred 5% or more of the time and at 1% or higher frequency in treated subjects compared to untreated subjects.
Row 8 reveals that 7% of the treated group and 5% of the untreated group caught the flu during the two years. Again, the difference between the groups is scientifically insignificant, and researchers may have thought it unlikely that the drug treatment was responsible, but good research required that it be reported.
And finally, we look at row 20. Here we see that chronic obstructive pulmonary disease, which can lead to stroke, affected 3% more subjects in the treated group. This was a significant enough finding that it bore watching, even though the rate of incidence was not unreasonable considering the age of the subjects. And as we discussed before, this did lead to follow-up study and an advisory letter to physicians.
These examples illustrate how those long-winded warnings on television come about. The possibility of experiencing any one of the side effects named is usually between one and three percent, but the law requires that we hear them all. And as they say, if you do experience side effects, no matter how minor, let your doctor know. Not just for your own health, but because you are on the forefront of the reporting process that keeps us all safe.
Adverse events can also occur as a result of our drug regimen interacting with other things we ingest. For this reason, it is important for us to inform our physicians and pharmacists of all the medications and supplements we are taking, and even the kinds of food we consume. Here are examples of some drug interactions that can affect many of us.
Supplements affecting drugs:
Vitamin E, Aspirin, Bilberry extract: Can increase anti-clotting activity and may cause an increased risk of bleeding when taken with a blood-thinning medication such as Coumadin (warfarin).
Ginkgo biloba: High doses could decrease the effectiveness of anticonvulsant drugs.
Drugs affecting drugs:
Antihistimines: Can cause a variety of problems in combination with sedatives, tranquilizers, or medication for high blood pressure or depression.
Cordarone (amiodarone): Can inhibit or reduce the effect of the blood thinner Coumadin (warfarin), and it can cause a rare, but serious kind of muscle injury if combined with Zocor (simvastatin).
Food or beverages affecting drugs:
Alcohol: If you are taking any sort of medication, it’s recommended that you avoid alcohol, which can increase or decrease the effect of many drugs.
Grapefruit juice: Can cause higher levels of certain medicines in your body.
Chocolate: Shouldn’t be consumed in excess with MAO (monoamine oxidase) inhibitors.
Fresh pineapple: Can increase the effects of sedative drugs, such as anticonvulsants, benzodiazepines and alcohol. Should not be combined with Amoxicillin or tetracycline antibiotics, as it can increase the amount of medication absorbed by the body.
TIPS TO AVOID PROBLEMS
The FDA offers these suggestions for taking medications in a safe and responsible manner.
- Always read drug labels carefully.
- Learn about the warnings for all the drugs you take.
- Keep medications in their original containers so that you can easily identify them.
- Ask your doctor what you need to avoid when you are prescribed a new medication. Ask about food, beverages, dietary supplements, and other drugs.
- Check with your doctor or pharmacist before taking an over-the-counter drug if you are taking any prescription medications.
- Use one pharmacy for all of your drug needs.
- Keep all of your health care professionals informed about everything you take.
- Keep a record of all prescription drugs, over-the-counter drugs, and dietary supplements (including herbs) that you take. Try to keep this list with you at all times, but especially when you go on any medical appointment.
The term “side effect” can also apply to consequences of a drug that were not originally intended, but that turn out to actually be beneficial. Sometimes, therefore, a drug is prescribed specifically because of a beneficial side effect. Use of drugs in such a way is termed “off-label” use. For instance, the anti-VEGF drug bevacizumab (Avastin) was designed and approved for use as a cancer treatment. It was found, however, to also be effective as a therapy for wet macular degeneration, diabetic retinopathy, and central retinal vein occlusion. Avastin is now being used as an off-label ophthalmic treatment alongside three drugs, Macugen, Lucentis, and Eyelea, which have been clinically tested and approved for use in the eye. This is legal practice, but before administering off-label drugs or procedures, your doctor is duty-bound to disclose the fact in writing and ensure that you fully understand any risks involved. You then have the right to refuse the drug and opt for an approved procedure if available.
Another example of therapeutic use of an off-lable drug is bupropion. Marketed as an anti-depressant under the name Wellbutrin, it was found to also be helpful for breaking the smoking habit. Bupropion was later approved by the FDA for that purpose, as well, so it is now also marketed for smokers, but under the name Zyban. One drug, two different labels. Problematic? Maybe, especially if you are being prescribed both products by two different physicians who aren’t aware of your prescription regimen. For this and other good reasons, doctors should be kept well-informed of your history.
Off-label use of drugs is legal, but marketing of drugs for unapproved indications is not. Pharmaceutical companies can be, and have been, fined for advertising their products as appropriate for conditions that have not been clinically proven to benefit from their use.
In addition, the FDA has established guidelines for off-label drug use by the health industry. The guidelines state that, before prescribing unapproved use of an approved or cleared medical product, health care professionals must receive truthful and non-misleading scientific and medical information from an unbiased, peer-reviewed scientific or medical journal article. In other words, a doctor must have clear evidence from a reputable source of a drug’s safety and efficacy before prescribing it for something other than its intended purpose.
Most of us have taken advantage of the lower cost of generic drugs, but are they as good or as safe as the original product? The quick answer is “yes”.
The FDA defines a generic drug as one that is comparable to an existing drug product in “dosage form, strength, route of administration, quality and performance characteristics, and intended use.” It may be marketed under its chemical name, rather than a brand name, or it may be marketed as a so-called “store brand”. It is subject to the same regulations as the original drug when it comes to formulation and labeling.
The time it takes a generic drug to appear on the market varies. In the US, a drug patent protects for 20 years from the beginning of the trials. And by the time it reaches the market, it may have only seven to twelve years left on its patent. This is one explanation for the high cost of some drugs, since the huge investment in research and development must be made up in only a few years.
Prescriptions are issued for drugs by their chemical names, so a prescription can be filled with a drug of any equivalent brand once it has gone generic. For example, a prescription for lansoprazole can be bought under names like Prevacid, Zoton, or Inhibitol. This gives you the option of shopping for the best price, so ask your pharmacist for a recommendation. If your physician recommends a drug to you by a brand name, or gives you a sample of a particular brand, again, ask if there is a generic substitute at a lower cost.
Another kind of substitute drug is called “biosimilar”. Drug molecules can either have synthesized chemical structures that can be duplicated, or they can be produced from living cells, all of which are slightly different. In the latter case, they are called biological drugs, and they cannot be duplicated exactly. The anti-VEGF drugs used in treatment of wet macular degeneration are biological. For those types of drugs to become legally interchangeable, scientists must show that the new product is highly similar and have no significant differences from the original product in terms of safety, purity, and potency. This requires additional clinical testing, and the so-called “biosimilar” drugs are governed under an extended set of rules.
All this is to help clarify that the anti-VEGF drugs currently being used for treating wet macular degeneration are not generic forms of the original drug. They are different molecules that perform in their own unique ways to block the growth of blood vessels in the retina. Due to the complexities and expense of creating and proving biosimilarity, it is unlikely that we will ever see less costly generic forms of those drugs.
So here is what we should remember about side effects from the drugs we use:
- The law says we must be told about every serious adverse event that may accompany a drug we are taking. But the odds are heavily in our favor that we will not be affected by any such events from a drug that has been clinically tested and approved.
- If a drug on the market is found to have serious adverse events, it must be reported by the physician to the manufacturer, and by the manufacturer to the appropriate government reporting center.
- You should be well-informed about the drugs you are administered and report any side effects to your physicians. It is the responsibility of your physician to ensure that you are aware of all potential side effects. Do not hesitate to ask questions before signing a consent form.
- Drugs can interact not only with other drugs, but with food and supplements, as well. Keep a record of all drugs and supplements you take, and be sure to give a copy to your physician and pharmacist. Also, if you develop a side effect, consider what food you have eaten that might have interacted with it.
- If your physician wants to use an off-label drug in your treatment, you will be asked to sign a waiver of responsibility. Be sure you understand all risks involved before agreeing.
- Drugs are understandably costly, so you can feel safe taking advantage of approved generic brands when they are available.
- We need not be frightened by the list of side effects that accompany the drugs we take. We should, however, be aware of them and report any such events to our physicians.
- All side effects and adverse events may not be identified during trials. It is important, therefore, that patients report all physiological and psychological changes during treatment, whether or not such changes are listed in the trial results and discussed in the prescribing information. This is both a personal and a public obligation that places us at the forefront of the reporting process.
I hope this helps you to better understand the sometimes complex issue of drug therapy and its potential side effects. I encourage you to pass this information along to others who might benefit.
To report side effects to the FDA:
Regular Mail: use postage-paid FDA form 3500 available at www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm
and mail to:
5600 Fishers Lane
Rockville, MD 20852-9787
Information for this presentation was gathered from the following resources:
Drug side effects montage: www.youtube.com/watch?v=7kY4Fx2BxdA
“Guidance for Industry – Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices” (FDA Department of Health and Human Services, January 2009)
“The First Year: Age-Related Macular Degeneration: An Essential Guide for the Newly Diagnosed” by Daniel L. Roberts (Marlowe & Co., New York City NY, 2006)
“Generic Drugs” (Center for Drug Evaluation and Research, U.S. Food and Drug Administration)
Personal notes from live panel discussions: “FDA Safety and Innovation Act: A Step Forward for Patients” and “Biosimilars: Implementing Sound Policies to Ensure Patient Safety” (Bio Patient and Health Advocacy Summit 2012, Washington, D.C.)