Drug Approval Process in the USA and Canada Does it guarantee the

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Drug Approval Process in the USA and Canada Does it guarantee the

International Biopharmaceutical Association Publication

    Drug Approval Process in the USA and Canada: Does it guarantee the

    patient's safety?

Samna Ghani

    1408-2350 Dundas St W

    Toronto ON M6P4A9

    Tel: 416-671-8714

International Biopharmaceutical Association Publication

     This article is based on the Drug Approval Process in the USA and Canada and evaluates whether the North American Drug Approval System guarantees the patient’s safety or not. It discusses the various procedures involved during drug approval and the existing FDA mode of operation for drug approvals. It also talks about the recent approvals and withdrawals of drugs in USA and their various reasons. The article aims to highlight the need for changes in the FDA policies and procedures to ensure patient safety. It identifies various loopholes in the drug approval system ranging from partiality to lack of financial resources.

    Drug Approval Process in the USA and Canada: Does it guarantee the patient's safety?

    The recent withdrawal of Vioxx from the market has brought FDA and its drug approval process in limelight and does raise the question: Does the drug approval process in USA and Canada really guarantee a patient's safety? After this incident, the FDA has been under strict surveillance and its credibility has indeed fallen. It has been accused of having a broken down regulatory system, of approving drugs without completely testing them, failing to follow up and monitor on unexpected side effects of drugs already in the market, of rushing drugs to the market etc. According to statistics obtained from the FDA itself, toxic reactions to marketed drugs are estimated to cost more than $30 billion per year and can be considered to be among the 10 leading causes of death in the United States.

    For most of the general public, a drug with FDA approval means that that particular drug is safe and has been properly evaluated. But how much does a general consumer know about the drug approval process in USA and Canada? How much does a general consumer know was identified, studied or examined about a particular drug? The general consumer only learns about a drug when he is either prescribed it, or when he hears that someone else was prescribed, or when he hears it on the news that a particular drug was launched and then withdrawn from the market after causing many injuries and sometimes, even death. The general consumer is, most of the time, unaware that the pharmaceutical companies play a major role in the approval of prescription drugs.

    Since 1997, more than a dozen drugs have been taken off the market due to severe side effects or injuries. This may come as a surprise to most US/Canadian consumers who believe that drug approvals by their health authorities guarantee that drug’s safety. They are unaware that when a drug goes on the market, only about 3,000 patients have ever been given that drug and that one never knows whether this drug may result in causing some harm to a patient maybe in 10,000 or 20,000. That would only be revealed once the drug is in the market and is being widely prescribed. And that would also be dependent on the fact that individual doctors and/or clinicians would identify a serious side effect and would actually report it to the FDA. That is a rare occurrence since most doctors report a drug’s side effect to the drug’s manufacturer. Then it’s on the company’s conscience whether it informs the FDA or not. This dependence on pharmaceutical companies to report any adverse events is not very reliable since its not guaranteed that all companies could be trusted to do so. There is no guarantee that these pharmaceutical companies wont hide this information just to avoid their product being pulled off the market or to avoid bad publicity.

    Thus the question again is: Does the drug approval process in the USA and Canada guarantee the patient’s safety? No it does not. This can be gauged from the following:

    1. Approval of a substantial number of drugs that have recently been approved and then withdrawn from

    the market as a result of safety problems

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    2. Delay in the removal from the market of some recently approved drugs

    3. Drugs banned in other countries for safety reasons, including recently approved drugs, which remain on

    the market in USA

    4. The conflict of interest created by the existing structure of FDA where the same personnel responsible

    for approving drugs have a central role in deciding whether a drug should be withdrawn or not due to

    reports or safety concerns.

    One may ask what exactly does it mean when a drug is “FDA Approved”. Does it mean that the drug is absolutely safe? Does it mean that the FDA and the prescribers know all possible side effects of this drug? Does it mean that the new drug is better than the older drugs available? Does it mean that the stamp of the FDA Approval guarantees patients’ safety? Does it mean an unconditional endorsement for the patients? The answer

    to all of these questions is No! Drugs are approved based on clinical trials. However, these clinical trials may not reveal all risks. Clinical trials usually include no more than a few thousand people taking the drug for a limited period of time. The ultimate test comes when a drug is in the market and is being used for longer periods of time. And here the health authorities have failed miserably at following up on a drug once it is out in the market. Moreover, FDA approval does not mean a new drug is superior to drugs already in the market for the same conditions. Many drugs are never even studied in comparison to older drugs to see whether they are really more effective or safe. Instead, most drugs are just compared with a placebo in clinical trials.

    There was a time when the FDA was accused of being too slow to approve new drugs and was depriving patients with drugs that might be beneficial for them. Due to these complaints, the Congress in 1992 passed a new law allowing the FDA to make its drug approval process much faster. Under the new law, the FDA was allowed to hire more reviewers and take the steps necessary to speed up reviews. The industry was supposed to bear the additional costs by paying the relevant fees with every new drug application. In this way, the industry got faster drug approvals and the FDA did not have to bear the additional cost. Although the new law created a faster review process, it also increased the risk of drugs being approved too quickly without complete information. Drug approval time dropped from 30 to 12 months on an average but this rush of new drug approvals opened the door for drugs being approved and marketed which could pose a threat to the patients taking them.

    The figure below shows the number of drugs per year approved by the FDA from 1939 to 2000. The significant increase in drug approvals can be clearly seen. On average, 3 drugs were approved per year in the 1940s, 10 in the 1950s, 11 in the 1960s, 17 in the 1970s, 28 in the 1980s, and 41 in the 1990s. In the last five years, however, almost 1 drug per week was approved in USA.

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    Figure 1. Number of drugs per year approved by the FDA for marketing in the United 6,7States

    Vioxx is in itself a case in point. The fact that the FDA actually suppressed information regarding risks associated with Vioxx has really caused a lot of damage to the public’s faith in the drug approval process

    overall. It is being said that the FDA threatened and intimidated one of its own drug safety scientists, Dr. David Graham, to prevent the publication of a study on Vioxx which showed the drug caused heart attacks in as many as 140,000 people. Of those, around 55,000 people may have died. According to David Graham, the Vioxx debacle is "maybe the single greatest drug-safety catastrophe in the history of this country". However, Vioxx is not the only “not so perfect drug” that has been given FDA approval. Public Citizen’s Health Research Group did a survey in 1998 of FDA medical officers and found 27 cases in which they said a drug was too dangerous to be approved but was approved over their heads anyway.

    There is a point of view that FDA partners up with the pharmaceutical industry and works with them rather than for the public health. This may be due to the fact that a large amount of FDA funding actually comes from the very companies who are seeking drug approvals. The extent of financial support which the industry provides to the FDA may be the reason why they have an extraordinarily dominating hold on the FDA making FDA a very partial player in the drug approval process overall. Obtaining evidence of side effects once the drug is in the market goes against the companies and therefore, the FDA conveniently fails to do so. In fact, while suppressing the evidence for Vioxx, the FDA has been accused of neglecting this information to protect the pharmaceutical industry.

    A USA Today study found that more than half of the experts hired to advise the government on the safety and effectiveness of medicine have financial relationships with the pharmaceutical companies that will be helped or hurt by their decisions. These are the experts who advise FDA on which drugs to be approved, what the warning labels should say and how the studies for the drugs be designed and conducted. USA TODAY found that 54% of the time, these experts have a direct financial interest in the drug or topic they are asked to

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    evaluate. Federal law generally prohibits the FDA from using experts with financial conflicts of interest, but the FDA has waived the restriction more than 800 times since 1998. A USA TODAY analysis of financial conflicts at 159 FDA advisory committee meetings from Jan. 1, 1998, through last June 30 found:

    ; At 92% of the meetings, at least one member had a financial conflict of interest.

    ; At 55% of meetings, half or more of the FDA advisers had conflicts of interest.

    ; Conflicts were most frequent at the 57 meetings when broader issues were discussed: 92% of

    members had conflicts.

    ; At the 102 meetings dealing with the fate of a specific drug, 33% of the experts had a financial


    ; At least one committee member had a financial stake in the topic under review at 146 of 159 FDA

    advisory committee meetings

    ; At 88 of those meetings, at least half the advisory committee members had financial interests in the

    topic being evaluated.

    How can approvals and judgments based on such shaky grounds be reliable? How would they be able to guarantee patients’ safety?

    Because of the Vioxx case, a lot of analysis has been made of the drug approval process in USA. Observers have expressed concerns that before a drug is marketed, the tests are usually small and focused on the effectiveness of the drug, ignoring the safety element to quite a great extent. The FDA does require 95% efficacy but does not have the same rigid criteria for safety and assumes that the drug is safe unless provided with data saying otherwise. It is the pharmaceutical companies who fund studies to prove the effectiveness of the drugs and the FDA does not have the funding to conduct studies on its own thus safety is an element which is somehow underplayed in this entire scenario.

    Most drugs are being aggressively marketed based on evidence from "academic research". However, no one really understands that most clinical research studies are sponsored by the companies marketing those drugs themselves and obviously, these companies look for researches for studies that will make their products look good. So how good and how reliable would this academic research be? Is it sufficient to guarantee a patient's safety? In a 1996 study in the Annals of Internal Medicine, Stanford University's Mildred Cho found that on average, 79% of papers on un-sponsored research reflected favorably on the drug in question and the percentage went up to 98% for papers on industry-sponsored research. So how reliable could this research and these clinical studies be? It is recommended that the government should increase funding for unbiased research so that there is more authentic and reliable data available with regard to the safety and efficacy of a new molecule.

    Of course, the pharmaceutical companies focus more on highlighting the benefits of a drug rather that its limitations. They do present the potential side effects of a drug but that message is quite secondary to the primary message of why the prescribers should prescribe the new drug. Most companies make a financial commitment when they develop, research and market a molecule. This financial commitment averages around $500,000, and these pharmaceutical companies would be the last ones to affect the product sales by highlighting the negatives of the drug! Moreover, why the pharmaceutical companies are in favor of speedy approvals is because they don’t want to waste more than necessary time for drug development and approvals. The more time used in this process, the less time the company would have to sell the drug while under patent. Thus,

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    reducing development and approval time is a major goal of most pharmaceutical companies. This results in companies conducting minimum studies, only those that are required and which fulfill the basic criteria for approval. A longer development time would mean more studies, which would mean even more investment and expense for the company. Thus, no one can really say for sure that 100% effort has been made during the development and approval process of a drug.

    The FDA is definitely not funded adequately to ensure proper fulfillment of its health and safety goals. Drug approvals should not only be based on safety and effectiveness prior to marketing approval, but also ensure continued safety monitoring after approval and once the drug is in the market. The problem however is, that the FDA does not have the resources to ensure the safety of drugs in the post-approval stage. FDA does focus on approval of new drugs but once these drugs are in the market, the FDA spends minimum funds or time to follow up or keep track of whether these drugs are causing any side effects in people who are taking them. There is an obvious negligence by the FDA on post-approval monitoring of drugs which is evident from the fact that the FDA has around 1300 employees helping process new drug applications, but only 72 employees who keep track of whether the newly marketed drugs are causing any side effects. So clearly, the FDA lacks emphasis on post-marketing surveillance. Currently, the FDA just approves new drugs and then sits around till some disaster takes place or doctors and/or patients bring it to the system's attention that some particular drug caused this particular side effect. Its like the FDA sits and waits around for bad news to pop in and hopes that none will! FDA also needs more resources to build consumer/patient databases and to increase the number of scientists on staff. Post marketing surveillance should be considered an essential element of a drug approval system. The health care system in North America seriously lacks in tracking the side effects of prescription drugs.

    The criteria for an effective drug approval system should not be the speed with which drugs are approved and brought into the market but instead, the drug approval system should be sound and comprehensive, ensuring approvals based on science rather than on pressure and speed. Once again, the FDA has been accused of catering to pharmaceutical companies and rushing new drugs into the market rather than ensuring safety of public health.

    Statistics show that six new drugs approved since mid-1996 have been pulled off the market. The irony is that all these six drugs were generic drugs and were for symptoms that were already treatable with existing medications. Nevertheless, millions of prescriptions were written, and more than 150 deaths were linked to these medicines before they were pulled off the market.

    During the past seven years, a growing number of drugs have been pulled from the market after the Food and Drug Administration had approved them. Here's a description of some of those drugs:

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    Drugs withdrawn from the market

    Brand Chemical What went Maker Used for Approved Withdrawn name name wrong

    Risk of heart

    attack and stroke Arthritis and Vioxx Rofecoxib Merck after 18 months 1999 2004 pain of continuous


    Reports of fatal


    A statin for a severe muscle Cerivastatin Baycol Bayer lowering disorder that may 1997 2001 sodium cholesterol damage organs

    and cause kidney


    Warner More toxic to Type 2 Rezulin Troglitazone Lambert/Parke-liver than similar 1997 2000 diabetes Davis medications.

    Use linked to

    liver failure, Bromfenac Duract Wyeth-Ayerst Pain relief leading to four 1997 1998 sodium deaths and eight

    liver transplants.



    High blood reactions Mibefradil Posicor Roche pressure and combined with 1997 1998 dihydrochloride chest pain any of more than

    25 other


    Linked to heart-

    valve problems Pondimin: and high blood

    Pondimin Fenfluramine pressure in the 1973, and Redux: Wyeth-Ayerst Weight loss lungs. Pondimin 1997 1996 Redux Dexfenflur-was the fen in the amine popular "fen-



    Linked to life-Hoechst An threatening Seldane Terfenadine Marion antihistamine 1985 1998 irregular Roussel for allergies heartbeats.

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    Company cited


    competition and

    falling sales for


    withdrawal. Nefazodone Bristol-Myers International and Serzone Depression 1994 2004 hydrochlor-ide Squibb Canadian health

    regulators had

    said its use could

    raise the risk of

    serious liver

    damage or liver


    Source: USA TODAY research

    New questions have been raised about the safety of some other drugs currently on the market. Here's a rundown

    on some of those drugs:

Approved drugs that have researchers concerned

    Brand Chemical Some health Maker Used for Approved name name risks

    In cancer-

    Arthritis, prevention trial, Celebrex Celecoxib Pfizer 1998 pain relief the risk of heart

    attack doubled.

    Heart problems

    in patients

    recovering from

    heart bypass Arthritis, Bextra Valdecoxib Pfizer surgery; some 2001 pain relief reports of


    potentially fatal

    skin reaction.

    Birth defects in

    pregnant women;

    Severe mental problems Accutane Isotretinoin Roche 1982 acne and suicides have

    been reported in


    Increased blood Sibutramine Weight Meridia Abbott pressure and 1997 hydrochloride loss heart rate.

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    Liver damage;

    small risk of

    rhabdomyolysis, Rosuvastatin Lowering Crestor AstraZeneca which is a serious 2003 calcium cholesterol deterioration of

    the muscles that

    can lead to death.


    Inhalant to asthma-related Salmeterol Serevent GlaxoSmithKline treat deaths and 1994 xinafoate asthma serious asthma



    Prevention aggression,

    Mefloquine of and paranoia, Lariam Roche 1989 hydrochloride treatment depression and

    for malaria thoughts of


    Source: USA TODAY research

    It is ironic that the core objective behind the FDA drug approval process is to ensure that only safe and effective drugs reach the marketplace and that drugs available for the public provide therapeutic benefits, which outweigh their risks to health. And yet the above quoted drug withdrawals and issues indicate that the FDA has been unable to achieve its objectives to quite a great extent. The FDA’s far too cozy relationship with the pharmaceutical industry should not be the criteria for drug approvals. Instead, it should be public health and safety that should be FDA’s main concern.

    Drugs out in the market may be FDA approved but that is no guarantee that they are going to be safe. That is because the FDA requires clinical testing in populations of only about 3000 people. That is a much smaller population keeping in mind the wide prescription base the drug could have once it’s in the market. For instance,

    if a drug turns out to be one that kills one in every 10,000 people, then that wont be seen TILL the drug is already out in the market. Moreover, there was a time when the FDA drug approval system was quite slow and so most drugs were first approved in Europe rather than in North America. That way the initial performance of the drug in terms of safety and efficacy could be gauged from there. However, since the aggressive approval approach taken on by FDA, 60% of new drugs come out in the US market first and the US patient population is thus the first one to be experimented on! The same can be said for Health Canada as Health Canada's drug approvals usually work in tandem with FDA. Health Canada also has a system that has low criteria for safety. Most of the time, health authorities only require that the drug be more effective than placebo. These health authorities should understand that simply working better than a placebo should not be the “only” criteria for

    approval. There must also be evidence that the benefit provided by the drug exceeds the risk that may be involved.

    Some FDA critics have proposed a solution to avoid disasters in drug approvals by creating a private organization solely responsible for new drug approvals. This organization would comprise of individuals

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    representing the drug industry, scientists and medical professionals. They would be the ones setting criteria for safety and efficacy of new drugs and would be responsible for reviewing all clinical data before making any decisions. One of the core reasons why this solution is being proposed is to reduce the supposed affiliation FDA has with the pharmaceutical companies and to ensure that its scientific merit alone which is the guiding principle for drug approvals. The independent private organization would be in a better position to avoid the political pressure because both Health Canada and FDA have not been totally fair to the public as they have been more focused on their partnership with the pharmaceutical industry and on speedy drug approvals.

    Secondly, the FDA is considered to be an inefficient bureaucratic agency that has failed the American public too many times. In fact, all the harsh rules and approval delays are for the smaller organizations while the giant firms, because of their hold on FDA, get away with most things without a problem. Drug approvals should be based on science and science alone, not on any political or financial motives that seem to be the case currently. Moreover, speedy drug approval should be for life-saving remedies and cures, not for every new drug that pharmaceutical companies claim to be wonder drugs but are offer nothing more than minor difference from existing therapies. Drugs like Vioxx are not life-saving drugs and thus there should be a requirement for more evidence on safety for such kind of drugs. Most recent painkillers, which include Vioxx, Celebrex and Bextra that have been approved by the FDA and widely prescribed to the public, filled no special need of the market. These patients could have done just as well with older, cheaper drugs and would have avoided the cardiovascular risks that have now been confirmed with the newer painkillers.

    On the other hand, abandoning the FDA altogether may be too drastic a solution. What some other critics suggest is a middle path where there would be an independent organization that would review the new drug proposals thoroughly and then would summarize its findings and recommendations and send it to the FDA. This independent organization would have sufficient say in deciding the criteria for new drug approvals and would play an active role in recommending changes and/or improvements to the drug approval process. In order to further enhance the role of this independent body, the FDA should be notified that they must approve/disapprove the new drug based on the recommendation of this independent body. If the FDA wishes to challenge this independent body's recommendation, it must provide clear and concise reasons for going against the recommendation.

    Based on all that has happened recently with drug approvals, withdrawals and other related issues; it is time that the FDA focused on the following areas:

    a. Drugs should be approved based on a pre-market research that would indicate whether there is need for

    this drug, whether there are equivalent existing therapies already available and what gap in that area

    needs to be fulfilled.

    b. FDA should be the one to start propagating and ensuring a quality assurance program where the players

    in the industry focus on safety and efficacy and the quality of products that are being applied for


    c. FDA should definitely increase its focus on Post-marketing surveillance. It should be vigorously active

    in keeping track of drugs once they are in the market in terms of their safety and efficacy.

    d. FDA should also focus on building and expanding on its internal resources to be better able to fulfill its

    commitment to the public and to ensure that maximum effort is made to examine a drug thoroughly.

    Following so much criticism after the Vioxx debacle, the FDA has already announced various steps it will be taking to improve its systems. It has announced that a top scientific body will review its drug safety system. It

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