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Although all of the women interviewed knew that Accutane should not be used during pregnancy, none reported having seen all the components of the Pregnancy Prevention Program.

Four women had not seen any of the educational material, aside from what was printed on the package. Most of the women interviewed did not use two forms of birth control—eight had not used contraception at all when the pregnancy occurred.

And only ten women took pregnancy tests before taking Accutane. The study highlighted that doctors continued to ignore many of the requirements of the Pregnancy Prevention Program. The CDC report also underlined the problem of overuse.

At least half of the respondents reported that they did not have the severe, recalcitrant, nodular acne for which the drug is indicated.

One woman described taking Accutane one week each month to prevent oily skin during her period. In part, the researchers linked increase use of the drug to advertising. Four of the respondents stated that commercials had contributed to their decisions to see a doctor. Within two months, Hoffmann-La Roche announced a new intervention, the Targeted Pregnancy Prevention Program, which would be geared toward the 0. The program consisted of a new batch of labeling changes; for example, two pregnancy tests should be timed according to instructions and performed before starting therapy; doctors should call pharmacists with prescriptions as opposed to handing written prescriptions to patients ; and two safe and effective methods of birth control should be used.

FDA approved the new label in May. A video would be distributed for doctors to show patients about the risks, and Roche would reiterate the importance of monthly pregnancy testing and counseling.

That spring, Roche distributed pregnancy tests to all doctors known to prescribe Accutane. The educational video for went out in June. And in July Roche began visiting individual prescribers to do office training. Jonca Bull posed the question to the Committee. The committee was to reflect on a variety of mechanisms—increased risk communication, modified packaging, restricted distribution, mandatory monitoring of patients, and improved informed consent—and formulate a general recommendation for FDA.

Hoffmann-La Roche presented data to the Committee suggesting that education would be the best way to reduce pregnancy. This reflected a need for more information about the importance of multiple forms of birth control and pregnancy testing.

Roche also presented figures that showed many doctors had failed to comply with the Pregnancy Prevention Program, prescribing the drug without first testing for pregnancy or obtaining a signed informed consent. Presumably, outreach efforts could achieve improved doctor participation and fewer pregnancies. A representative of Celgene, the U. In addition, all patients participated in a mandatory survey tracking their Thalidomide use.

At that time, about 10, pharmacies and doctors had enrolled in the program. Dermatologists voiced objections to restricted access programs. Reed suggested that the system would disrupt the doctor-patient relationship and force patients to find new doctors just to start a new treatment. Compelling patients to discuss sex and pregnancy with an unfamiliar doctor would undermine education efforts. Patients in rural communities might have to travel long distances to get needed care.

I am convinced that education. The committee voted for a form of restricted access. In addition to increasing educational efforts, as Roche suggested, the Pregnancy Prevention Program should be modified: all prescriptions should be limited to 30 day-supplies, and before dispensing Accutane, pharmacists should have to confirm that a negative pregnancy test has been documented. For women taking the drug, registration in the Program should be mandatory as should participation in the Slone survey.

Previously, participation in the survey had been voluntary, and Committee members worried that the data were inaccurate. The Committee also recommended that Roche be required to conduct independent surveillance to identify pregnancy exposures. Upon receipt of the letter, Roche will send prescribers yellow qualification stickers.

All prescriptions for Accutane should have attached a special yellow sticker, which indicates that the patient has had a negative pregnancy test and counseling about pregnancy prevention. The pregnancy test will be repeated every month before a new prescription is provided. Pharmacists will only be permitted to fill prescriptions that have the yellow sticker. In addition, all female patients must be given the opportunity to participate in the Slone survey.

Participation will not be mandatory. Clearly, the program was designed as a compromise between the desire for European-styled programs which achieve very low rates of pregnancy exposure by strictly limiting access, and the conflicting goal of easy availability of medicine to those who need it. But, while the program may look like a form of restricted access—after all, only doctors with special yellow stickers can prescribe the drug—in actuality the new protections more serve as hoops to jump through than barriers to access.

Any doctor can send in a Letter of Understanding and obtain the stickers; qualification is not limited to dermatologists or other healthcare providers with special training. And like the Letter of Understanding, the sticker itself amounts to nothing more than a statement by a doctor of self-certification. The yellow sticker signifies that a patient has received pregnancy tests and counseling, not that a patient has severe cystic acne.

Clearly, SMART caters to the concerns expressed by dermatologists at the September meeting: whether or not a patient obtains a prescription to Accutane remains almost entirely in the control of the physician.

A few modifications might have given this certification-based form of restricted access more teeth. For one, Roche might have made its half-day continuing medical education class a mandatory prerequisite for certification instead of a recommended event.

In that way, the company would have ensured that doctors who receive stickers actually have been informed of the best practices. Then it would have been impossible for a doctor to prescribe the drug if he forgot to perform a pregnancy test. In order to write a prescription without performing two tests, a doctor would have to actively forge the documentation.

At very least, FDA might have included a diagnosis of severe, recalcitrant acne as one of the preconditions for using the yellow sticker; this would have sent a clear message that Accutane was not appropriate for off-label use. As it stands, doctors are their own gatekeepers, and their judgment and neglect remain unchecked. Presumably, many doctors will actually read the Guide to Best Practices before submitting the letters and will benefit from the increased education.

In addition the yellow stickers might serve as a reminder, triggering doctors to perform pregnancy tests and provide counseling. Taken together the yellow stickers and letter of certification might be interpreted as a contract, and doctors who use the stickers without the requisite protections might be liable for their actions.

The precautions signified by the sticker suggest a clear standard of care required for the profession. Maybe the specter of the litigation that might arise from misuse of the stickers will be enough to scare doctors into compliance. More generally, the very fact of such a novel program will undoubtedly convey the message that Accutane poses serious risks and should not be prescribed casually.

The primary focus of future of Accutane regulation may be mental illness. As of December 31, , Accutane users worldwide 94 in the U. Another patients have been hospitalized for severe depression or attempted suicide. About 6. Perhaps because of its prior experiences, FDA has been quicker to require Hoffmann-La Roche warn about the possibility of depression and suicide, even in the absence of clear evidence. In June when FDA mandated a black box warning for Accutane, depression was included as one of the possible side effects that had been reported.

On February 24, Roche released a new label. The warning began:. Psychiatric Disorders: Accutane may cause depression, psychosis and rarely, suicidal ideation, suicide attempts and suicide. Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary.

No mechanism of action has been established for these events. A month later, the United Kingdom required a similar warning. According to FDA, doctors should simply act as if Accutane causes suicide. In March , Hoffmann-La Roche published a medication guide that explains the possible association between suicide and Accutane to patients. The company also unveiled a new informed consent form, which describes the concern about suicide and requires patients inform their doctors of any history of mental illness.

This spring the company will send out a new brochure to dermatologists and other prescribing physicians instructing them how to recognize early signs of depression. But Hoffmann-La Roche has also indicated a familiar reluctance to disclose information.

Only in July , 14 months after FDA first approached Hoffmann-La Roche about adding suicide to the warning label, did the agency discover that a French study from showed an association between Accutane and depression. And like Accutane-induced birth defects, cases of suicide and depression have generated new adversaries for Hoffmann-La Roche—adversaries driven to take action.

On its website the group describes the mission:. One ally of the group is Michigan Congressman Bart Stupak. Congress postponed the hearing after September 11th. But in the aftermath of September 11th, one particular case brought the association between Accutane and suicide back into the spotlight. On January 5th, year-old Charles Bishop flew a small plane into an office building in Tampa, Florida. According to an analyst quoted in the New Jersey Record, Accutane sales have dropped by ten percent since because of increased publicity of Accutane-linked suicides.

The manufacturer and FDA continue to struggle with this the highly publicized—but poorly understood—phenomenon. Without doubt, Accutane is a special drug, one that poses extraordinary challenges for FDA. By pushing FDA to devise new control techniques, Accutane left its mark on the agency. Although the drug itself remains unique, the story of Accutane provides insight into drug regulation in the United States generally.

It is also worth noting how much of the story has been driven by circumstance. Had more babies been deformed by Thalidomide—as they were in Europe—fewer would have been exposed to Accutane.

And politics have influenced regulation in other ways as well. In considering where to point fingers in the Accutane story, we should remember that some portions must be owed to fortuity. If we conceive of FDA as a safety net designed to protect consumers, then perhaps Accutane babies might be said to have fallen through the holes. For one, FDA has no authority over doctors or patients, the two groups who ultimately control whether a fetus will be exposed to Accutane.

A clear conclusion to be drawn from this story is that Dear Doctor letters and warnings on labels do not effect significant change on the part of healthcare practitioners. This inability to control directly the gatekeepers to prescription drugs poses a real limitation for the agency. Products whose safety depends on behavioral practices will inevitably reach beyond the scope of FDA.

The story also raises fundamental concerns about the advisory committee system put in place by FDA. Are the doctors who would use a particular drug well-suited to decide whether it should be allowed on the market? Accutane provides revenue not only for Hoffmann-La Roche but also for the doctors prescribing it, most of whom are dermatologists. Each of the five million Americans who have used Accutane visited a doctor to obtain a prescription.

Weight between 40 and kg. Negative serum human chorionic gonadotropin hCG pregnancy test consistent with a non-pregnant state females only. No significant disease or clinically significant finding in a physical examination. No clinically significant abnormal laboratory value. No clinically significant abnormal vital sign measurement.

Patients presenting with stable and controlled diabetes mellitus Types I and II may be included in the study. However, patients should not have had a hospitalization for any diabetes related complications in the last 12 months, and must be on stable medication for the preceding 6 months.

Patients with previously diagnosed Polycystic Ovarian Syndrome PCOS may be included in the study if in the opinion of the investigator they do not have any other clinically significant abnormality e. Exclusion Criteria: Female patients will be excluded from the study if they: Are pregnant; Are at high risk for becoming pregnant or likely to become pregnant during treatment; Will be breast-feeding or considering breast feeding during the course of the study.

Known history or presence of any clinically significant unstable medical condition s which in the opinion of the investigator could pose a risk for the safety of the patient including any previous history of gastrointestinal disease. Patients with any skin disease or other condition that might interfere with the evaluation of recalcitrant nodular acne. Patients with a lifetime history of psychosis will be excluded. Patients with a history of major depressive, manic, hypomanic or mixed episodes will not be excluded unless they have had an episode during the preceding year.

Patients with any past or current psychotic symptoms. Patients reporting any suicidal behaviour including attempts, interrupted attempts, aborted attempts, or other preparatory behaviours , within the past year, or serious suicidal ideation in the past year, will be excluded from study participation. A lifetime history of wishing to be dead, non-specific active suicidal thoughts or active suicidal ideation without intent to act will not result in exclusion.

Known history or suspected carcinoma. Known history of liver or kidney disorders hepatic and renal insufficiency. Known history or current pseudotumor cerebri benign intracranial hypertension. Patients with hearing disorders who in the opinion of the investigator would not be able to participate in audiometric testing for the study. Allergy to soy beans, soy bean oil or any other ingredients in the study medications.

On a special diet within four weeks prior to drug administration e. Difficulty consuming two 2 meals a day to sustain weight and health. Contacts and Locations. Search tools. Select Date Range: to. Select Rare Disease:. IMP with orphan designation in the indication. Orphan Designation Number:. Results Status: Trials with results Trials without results.

Clear advanced search filters. EudraCT Number: Trial protocol: GR Completed. Trial results: View results. Trial protocol: DK Ongoing. Trial results: No results available. Trial protocol: DE Completed. Full Title: A randomized, partially blinded, parallel study to evaluate the effects of nacystelyn in combination with isotretinoin in the treatment of recalcitrant acne vulgaris.

Trial protocol: BG Completed. Full Title: Pilot study to investigate the feasibility of cis-Retinoic acid pharmacokinetic monitoring in high-risk neuroblastoma.

 


Patients’ Knowledge and Information Needs about Isotretinoin Therapy Use in Jordan.



 

The acne drug Accutane is one of the most dangerous products on the market today. The drug causes serious side-effects, most notably birth defects. Accutane is also one of the most effective prescription drugs available. This combination—unique efficacy coupled with unique risk—has posed a serious challenge for the Food and Drug Administration FDA. Over the past two decades, FDA has grappled with how manage the completely preventable but persistently serious problem of Accutane-induced birth defects.

On several occasions, the product spurred FDA to take unprecedented regulatory action. In when American researchers for Hoffmann-La Roche began studying the chemical, isotretinoin, they were struck by its remarkable effectiveness.

This may seem like undue attention for a simple pimple remedy, but in actuality severe acne can be a seriously debilitating condition. Much more than the familiar blackheads, the condition is marked by tremendous pus filled lesions which typically spread across the entire face and neck leaving behind pitted scars.

One FDA official noted that the cysts can be so "cosmetically crippling that people cannot get jobs. I am now confident, happy and very excited about life. I no longer feel inferior and can actually look people in the eyes.

About 12 million people worldwide including 5 million Americans have taken Accutane, which is called Roaccutane outside the United States. But as productive as it is, both as a money-maker and a therapy, Accutane also has the potential to destroy lives. Accutane is an extremely dangerous teratogen: it can cause severe birth defects when taken during pregnancy. About one quarter of babies born who have been exposed to Accutane during gestation have major congenital deformities. Those babies born without major malformations frequently develop severe learning disabilities.

Edward Lammer, a medical geneticist and consultant to FDA, describes the overall risk posed by Accutane:. This is an extraordinarily high absolute risk, really comparable, in terms of environmental exposures, only to Thalidomide or certain congenital infections. There is no other medication that poses an absolute risk anything remotely close to this, even medications used to treat cancer during pregnancy. According to Dr. Lammer, brain abnormalities are the most typical problem for Accutane babies, even babies who appear normal at birth i.

In addition, Accutane commonly inhibits the development of the bones and cartilage of the face. Children may be born with no ears at all; sometimes there are small slits in the place of ears. Heart defects, which often grow fatal, characterize the third most common problem described by Dr. Since its approval in , references to Accutane have peppered the pages of law reviews and other publications. The drug has become an example for academics and others proposing reform.

But none of these accounts has offered a full history of Accutane in the U. This paper takes a journalistic approach, tracing the chronology of Accutane in the U. Accutane has repeatedly pushed the frontier of FDA regulation, as the agency struggled to adapt its tools to meet the challenge of an extremely effective and extremely dangerous medication.

By emphasizing the evolving American response to the high level of risk associated with Accutane, I hope to provide the material needed to evaluate the strengths and weaknesses of our current regulatory framework.

Discovery and Pre-Market Approval : Perhaps the biggest challenge in chronicling Accutane has been to decipher the early history of the drug. Creating a narrative has required piecing together fragments of the puzzle which surfaced over the course of the past decade. One might blame Roche: the company has repeatedly gone to court demanding that material describing the development of Accutane be kept private. But some believe that the Roche exploits that authority in order to keep certain details—details which might reflect poorly on the company—obscured.

Werner Bollag first studied the chemical compound, cis retinoic acid at Roche laboratories in Switzerland during the s. But Bollag also realized that the drug could cause serious birth defects. The compound derived from vitamin A, a known teratogen. When it proved ineffective as a cancer therapy he abandoned the project. In their research, Drs. Frank Yoder and Gary Peck accidentally discovered that the chemical also cleared up acne.

Subjects who had been covered with pimples returned to the office with clear skin. Isotretinoin became Accutane, and in clinical trials researchers carefully avoided exposing pregnant women to the drug. Hoffmann-La Roche had conducted animal studies, and offspring of subjects showed facial deformities much like the ones that have subsequently been seen in Accutane babies.

Those researchers who did include women in trials required a negative pregnancy test and contraceptive use. FDA provides administrative support to the Dermatologic Drugs Advisory Committee, which includes several dermatologists, other medical experts and a consumer representative.

But the Committee also urged that the label be revised. There are no adequate and well-controlled studies in pregnant women. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Although FDA heightened the pregnancy risk rating for the drug, the original label did not suggest the careful precautions that Roche itself had used during clinical trials. Instead, the label noted the fact that there had been no evidence of birth defects in humans.

In May , nine months after the application had been submitted, FDA announced approval of Accutane. According to a Hoffmann-La Roche spokeswoman quoted in the Washington Post , "Approval came through so fast that it came as quite a surprise to everyone The United States was the first country to approve Accutane.

In September , Accutane arrived to a warm welcome. News and World Reports stated that Accutane could clear up most cases of acne within a few months. At the same time, some of the doctors who had studied the drug began to voice alarm. Henry J. Roenigk had been chairman of the dermatology department at Northwestern University and participated as a researcher for Roche during clinical trials. The potential toxicity of this drug has been seriously under-emphasized.

Hoffmann-La Roche reproached the scientists for releasing information obtained while working for the company. Yoder claims that he received a hostile phone call from Roche executives. According to him, Roche representatives ''angrily told me I should not be writing that sort of confidential information.

I didn't agree with them. I thought the public good must be served. Shortly afterward the company sent letters to all scientists who had participated in clinical trials, stressing the confidentiality of information obtained during research sponsored by Hoffmann-La Roche. Within a few months, Hoffmann-La Roche began receiving stories about of babies born with severe birth defects to women who had taken Accutane.

In June —nine months after the drug had been released—three cases were reported to Roche. The company also revised the drug label to include more information about birth defects and a more prominently placed warning. In addition, Public Citizen asked FDA to require patient package inserts explaining the possible side-effects in non-technical language.

In the first 18 months of marketing, about , patients took Accutane. By March , Roche collected reports of 20 Accutane babies. The label explicitly suggested that patients use contraceptives beginning a month before therapy.

In addition, FDA advised blood banks to refuse donations from Accutane users. Between and Roche delivered seven more Dear Doctor letters warning about Accutane. Practitioners have suggested that FDA requires a black box warning when it hopes to decrease sales of a drug. On April 22, four days before the scheduled meeting, an account of the confidential FDA memo appeared on the front page of the New York Times. News of the large estimated number of Accutane babies—combined with the large number of abortions suggested to have been caused by the drug—sparked a craze of media attention.

Journalists questioned whether the manufacturer and doctors had pushed the drug too far and whether FDA had approved the drug too quickly. We must not allow the advisory committee process to be used as an excuse to permit such a seriously birth-deforming drug to remain on the market.

Yoder also described the firm safeguards that had been in place during testing to ensure that no pregnant women were exposed to the drug. This was very, very wrong. One source of controversy was the disparity between Accutane use in the U.

As of April 30, only three Accutane babies had been born in Europe. In Switzerland, doctors had to register with the government to prescribe it. In the United Kingdom, only dermatologist had authority to prescribe Accutane and only hospitals could dispense it.

As a prerequisite to receiving the drug in Britain, a woman had to stipulate that she would be willing to have an abortion. Sweden never approved Accutane for general use; dermatologists applied for special permission when a patient had a particular need.

In Spain, the Ministry of Health kept the name and address of every woman taking Accutane in a special registry. The European approach to Accutane reflected not just a different regulatory methodology, but also differing circumstances. In the wake of Thalidomide, Europeans treated all teratogenic drugs extremely cautiously. The Committee meeting on April 26th was just as contentious as the public debate that preceded it. Hoffmann-La Roche proposed an aggressive education program to reduce the risk of pregnancy.

The Committee recommended that only a limited number of certified physicians be permitted to dispense the drug. In addition, women at high-risk of pregnancy would be required to procure a second opinion before receiving Accutane. Questioning whether it had the authority to dictate who could prescribe the drug, FDA instead mandated new warnings for the label.

The agency required that Hoffmann-La Roche provide informed consent forms to be signed by patients and doctors. In addition the FDA directed the company to double the type size in the warning; include a picture of a baby deformed by Accutane in the material going to patients; dispense the drug in a blister-pack with warnings on every package; instruct doctors that they should give both written and oral warnings; add a symbol of a pregnant woman crossed out on the material given to doctors and patients; and conduct follow-up studies to determine the efficacy of the new program.

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Clinical Trials Register.Thoughts on Accutane:



    However, more than half of them Cahusac, and D. Trial protocol: DE Completed. The cover letter also informed the patients that their participation is voluntary and the data will be kept confidential. Are the doctors who would use a particular drug well-suited to decide whether it should be allowed on the market? In , each of these three adversaries brought Hoffmann-La Roche to court. Hoffmann-La Roche, N.

Demographic characteristics of the study participants are presented in Table 1. The majority of the patients Most of the patients Other side effects including itching, rash, nosebleeds, joint and back pain, dizziness, eye inflammation, depression, and increased liver enzymes were recognized by less than half of the patients. Among the seventeen married female patients who participated in this study, only one patient used isotretinoin without oral contraceptives, two patients were not informed by the physician or the pharmacist about the risk of teratogenicity of isotretinoin, and three of them did not make pregnancy test on a monthly basis.

The study patients showed good knowledge about isotretinoin use with a mean total knowledge score of 8. As shown in Table 2 , more than half of the patients As shown in Table 3 , the t -test reported that female gender 8. Results showed that only 1. However, nearly Approximately one-third of the patients However, due to concerns about its side effects and its potential to cause birth defects in particular, the medication was not released to the market until [ 19 ].

Isotretinoin is, by far, the most cost-effective drug when compared with other medications used for severe acne treatment. However, it has been associated with some serious and teratogenic adverse effects that patients must be aware of [ 2 — 4 ]. The majority of this study patients Similar results were reported by Kara Polat On the contrary, an earlier Saudi study [ 22 ] reported that the most identified source of information for isotretinoin therapy was friends, followed by the internet and social media.

However, most of the current study patients advised others to use isotretinoin based on their old experience, which might increase the potential of medication side effects. Consistent with earlier study findings [ 9 , 12 , 20 — 22 ], dryness was the most commonly recognized side effect of isotretinoin therapy. The majority of the current study participants were not able to recognize side effects of isotretinoin therapy such as itching, rash, nosebleeds, joint and back pain, dizziness, eye inflammation, depression, and increased liver enzymes.

In comparison, only In addition, around half of the isotretinoin users enrolled in another study were not able to recognize depression as a side effect of isotretinoin therapy [ 21 ]. Comparable with earlier Saudi study finding [ 21 ], some patients were not able to recognize dyslipidemia as a side effect of isotretinoin therapy in the current study.

Although the majority of the present study patients recognized teratogenicity as a side effect, higher percentages were reported in earlier studies [ 9 , 12 ]. Lack of knowledge about isotretinoin side effects in this study could be attributed to the availability of isotretinoin without prescription, which could lead to the missing out of physician explanation about isotretinoin side effects and might make the patients feel that the drug is safe. In other words, married female patients who are prescribed isotretinoin must perform pregnancy test before and during the treatment course in order to avoid birth defects [ 24 ].

Consistent with earlier Saudi and Canadian studies [ 25 , 26 ], some married female patients in the present study were not informed by the physician or the pharmacist about the teratogenicity of isotretinoin and did not perform pregnancy test on a monthly basis while using the drug. In the present study, the patients demonstrated poor knowledge about the appropriate duration of isotretinoin therapy and its combination with fatty meal and sunblock.

In order to achieve the optimal therapeutic response to isotretinoin therapy, it should be taken for four to six months depending on the daily dose given [ 27 ]. Those babies born without major malformations frequently develop severe learning disabilities. Edward Lammer, a medical geneticist and consultant to FDA, describes the overall risk posed by Accutane:. This is an extraordinarily high absolute risk, really comparable, in terms of environmental exposures, only to Thalidomide or certain congenital infections.

There is no other medication that poses an absolute risk anything remotely close to this, even medications used to treat cancer during pregnancy. According to Dr. Lammer, brain abnormalities are the most typical problem for Accutane babies, even babies who appear normal at birth i.

In addition, Accutane commonly inhibits the development of the bones and cartilage of the face. Children may be born with no ears at all; sometimes there are small slits in the place of ears. Heart defects, which often grow fatal, characterize the third most common problem described by Dr. Since its approval in , references to Accutane have peppered the pages of law reviews and other publications.

The drug has become an example for academics and others proposing reform. But none of these accounts has offered a full history of Accutane in the U. This paper takes a journalistic approach, tracing the chronology of Accutane in the U. Accutane has repeatedly pushed the frontier of FDA regulation, as the agency struggled to adapt its tools to meet the challenge of an extremely effective and extremely dangerous medication.

By emphasizing the evolving American response to the high level of risk associated with Accutane, I hope to provide the material needed to evaluate the strengths and weaknesses of our current regulatory framework. Discovery and Pre-Market Approval : Perhaps the biggest challenge in chronicling Accutane has been to decipher the early history of the drug.

Creating a narrative has required piecing together fragments of the puzzle which surfaced over the course of the past decade. One might blame Roche: the company has repeatedly gone to court demanding that material describing the development of Accutane be kept private. But some believe that the Roche exploits that authority in order to keep certain details—details which might reflect poorly on the company—obscured. Werner Bollag first studied the chemical compound, cis retinoic acid at Roche laboratories in Switzerland during the s.

But Bollag also realized that the drug could cause serious birth defects. The compound derived from vitamin A, a known teratogen. When it proved ineffective as a cancer therapy he abandoned the project. In their research, Drs.

Frank Yoder and Gary Peck accidentally discovered that the chemical also cleared up acne. Subjects who had been covered with pimples returned to the office with clear skin. Isotretinoin became Accutane, and in clinical trials researchers carefully avoided exposing pregnant women to the drug. Hoffmann-La Roche had conducted animal studies, and offspring of subjects showed facial deformities much like the ones that have subsequently been seen in Accutane babies.

Those researchers who did include women in trials required a negative pregnancy test and contraceptive use. FDA provides administrative support to the Dermatologic Drugs Advisory Committee, which includes several dermatologists, other medical experts and a consumer representative. But the Committee also urged that the label be revised. There are no adequate and well-controlled studies in pregnant women. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

Although FDA heightened the pregnancy risk rating for the drug, the original label did not suggest the careful precautions that Roche itself had used during clinical trials. Instead, the label noted the fact that there had been no evidence of birth defects in humans. In May , nine months after the application had been submitted, FDA announced approval of Accutane. According to a Hoffmann-La Roche spokeswoman quoted in the Washington Post , "Approval came through so fast that it came as quite a surprise to everyone The United States was the first country to approve Accutane.

In September , Accutane arrived to a warm welcome. News and World Reports stated that Accutane could clear up most cases of acne within a few months. At the same time, some of the doctors who had studied the drug began to voice alarm. Henry J. Roenigk had been chairman of the dermatology department at Northwestern University and participated as a researcher for Roche during clinical trials.

The potential toxicity of this drug has been seriously under-emphasized. Hoffmann-La Roche reproached the scientists for releasing information obtained while working for the company. Yoder claims that he received a hostile phone call from Roche executives.

According to him, Roche representatives ''angrily told me I should not be writing that sort of confidential information. I didn't agree with them. I thought the public good must be served. Shortly afterward the company sent letters to all scientists who had participated in clinical trials, stressing the confidentiality of information obtained during research sponsored by Hoffmann-La Roche.

Within a few months, Hoffmann-La Roche began receiving stories about of babies born with severe birth defects to women who had taken Accutane. In June —nine months after the drug had been released—three cases were reported to Roche. The company also revised the drug label to include more information about birth defects and a more prominently placed warning.

In addition, Public Citizen asked FDA to require patient package inserts explaining the possible side-effects in non-technical language.

In the first 18 months of marketing, about , patients took Accutane. By March , Roche collected reports of 20 Accutane babies. The label explicitly suggested that patients use contraceptives beginning a month before therapy.

In addition, FDA advised blood banks to refuse donations from Accutane users. Between and Roche delivered seven more Dear Doctor letters warning about Accutane.

Practitioners have suggested that FDA requires a black box warning when it hopes to decrease sales of a drug. On April 22, four days before the scheduled meeting, an account of the confidential FDA memo appeared on the front page of the New York Times.

Full Title: A randomized, partially blinded, parallel study to evaluate the effects of nacystelyn in combination with isotretinoin in the treatment of recalcitrant acne vulgaris. Trial protocol: BG Completed.

Full Title: Pilot study to investigate the feasibility of cis-Retinoic acid pharmacokinetic monitoring in high-risk neuroblastoma. Trial protocol: GB Completed. Trial protocol: FR Ongoing. Full Title: Relative bioavailability and comparative pharmacokinetics of CRA oral liquid and extracted capsule formulations: a randomised, open label, multi-dose, cross-over clinical trial in patients requi Trial protocol: IT Prematurely Ended.

Full Title: Phase 2 trial evaluating metronomic chemotherapy in patients with relapsed or refractory Wilms tumor. Trial protocol: IT Ongoing. Patients with any past or current psychotic symptoms. Patients reporting any suicidal behaviour including attempts, interrupted attempts, aborted attempts, or other preparatory behaviours , within the past year, or serious suicidal ideation in the past year, will be excluded from study participation.

A lifetime history of wishing to be dead, non-specific active suicidal thoughts or active suicidal ideation without intent to act will not result in exclusion. Known history or suspected carcinoma. Known history of liver or kidney disorders hepatic and renal insufficiency. Known history or current pseudotumor cerebri benign intracranial hypertension. Patients with hearing disorders who in the opinion of the investigator would not be able to participate in audiometric testing for the study.

Allergy to soy beans, soy bean oil or any other ingredients in the study medications. On a special diet within four weeks prior to drug administration e. Difficulty consuming two 2 meals a day to sustain weight and health. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials. Layout table for investigator information Study Chair: James J.

Warning You have reached the maximum number of saved studies Weekly Isotretinoin Therapy Study WIT The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.

Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Results First Posted : May 9, Last Update Posted : May 9, Study Description. The mainstay of treatment for moderate acne remains long courses of oral antibiotics despite emerging antibiotic resistance. The efficacy of daily to twice daily dosed isotretinoin, an oral vitamin A derivative, for treatment of severe acne has been well established. The purpose of this study is to determine if once weekly dosed isotretinoin is effective for the treatment of patients with moderate acne.

Additionally, the study aims to evaluate patient satisfaction and identify any adverse effects on this alternative dosing regimen. Detailed Description:. Drug Information available for: Isotretinoin. FDA Resources.

Arms and Interventions. Outcome Measures. Participants will fill out a survey regarding nonserious and serious adverse events. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision.

Study record managers: refer to the Data Element Definitions if submitting registration or results information. Active Comparator: Isotretinoin Drug: Isotretinoin 0. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.

To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Female patients will be excluded from the study if they:. We're building a better ClinicalTrials. Check it out and tell us what you think! Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information.

Search for terms. Save this study. Warning You have reached the maximum number of saved studies Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Results First Posted : July 4, Last Update Posted : July 4, Study Description.

The purpose of this study is to compare the efficacy and safety of CIP-Isotretinoin and a marketed generic formulation of isotretinoin when both are administered twice daily with meals. Drug Information available for: Isotretinoin. FDA Resources. Arms and Interventions. Outcome Measures. A grade of either 0 clear or 1 almost clear on the 6-point PGSA scale within the Week 20 analysis window was considered a success. Eligibility Criteria.

Inclusion Criteria: Severe recalcitrant nodular acne, which in the opinion of the investigator is compatible with isotretinoin treatment. Age between 12 and 54 years. Weight between 40 and kg. Negative serum human chorionic gonadotropin hCG pregnancy test consistent with a non-pregnant state females only. No significant disease or clinically significant finding in a physical examination. No clinically significant abnormal laboratory value. No clinically significant abnormal vital sign measurement.

Patients presenting with stable and controlled diabetes mellitus Types I and II may be included in the study. However, patients should not have had a hospitalization for any diabetes related complications in the last 12 months, and must be on stable medication for the preceding 6 months.

Patients with previously diagnosed Polycystic Ovarian Syndrome PCOS may be included in the study if in the opinion of the investigator they do not have any other clinically significant abnormality e.

Exclusion Criteria: Female patients will be excluded from the study if they: Are pregnant; Are at high risk for becoming pregnant or likely to become pregnant during treatment; Will be breast-feeding or considering breast feeding during the course of the study.

Known history or presence of any clinically significant unstable medical condition s which in the opinion of the investigator could pose a risk for the safety of the patient including any previous history of gastrointestinal disease. Patients with any skin disease or other condition that might interfere with the evaluation of recalcitrant nodular acne.

Patients with a lifetime history of psychosis will be excluded. Patients with a history of major depressive, manic, hypomanic or mixed episodes will not be excluded unless they have had an episode during the preceding year. Patients with any past or current psychotic symptoms. Patients reporting any suicidal behaviour including attempts, interrupted attempts, aborted attempts, or other preparatory behaviourswithin the past year, or serious suicidal ideation in the past year, will be excluded from study participation.

A lifetime history of wishing to be dead, non-specific active suicidal thoughts or active suicidal ideation without intent to act will not result in exclusion. Known history or suspected carcinoma.

Known history of liver or kidney disorders hepatic and renal insufficiency. Known history or current pseudotumor cerebri benign intracranial hypertension.

Patients with hearing disorders who in the opinion of the investigator would not be able to participate in audiometric testing for the study. Allergy to soy beans, soy bean oil or any other ingredients in the study medications. On a special diet within four weeks prior to drug administration e.

Difficulty consuming two 2 meals a day to sustain weight and health. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials.

Layout table for investigator information Study Chair: James J. More Information. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.

Severe Nodular Acne. Phase 3. Study Type :. Interventional Clinical Trial. Actual Enrollment :. Study Start Date :. Actual Primary Completion Date :. Actual Study Completion Date :. Drug: CIP-Isotretinoin 0. Drug: Isotretinoin 0. Philadelphia, Pennsylvania, United States, September 11, Key Record Dates.

A phase of research to describe clinical trials that gather more information about a drug's safety and effectiveness by studying different populations and. Clinical studies and global experience have shown that ISO provides complete or nearly complete remission of acne, with sustained therapeutic benefit after. In , clinical trials' results revealed that isotretinoin was ineffective for treating skin cancer, but could be useful for the management of AV. localhost Identifier, Title, Drugs. NCT, Efficacy and Safety of CIP-Isotretinoin in Patients With Severe Recalcitrant Nodular Acne. Finally, 25 randomized controlled clin- ical trials (RCTs) and five open-label clinical trials provided acne vulgaris suffering patients. Secondary Outcome Measures : Number of Participants With a Change in Quality of Life [ Time Frame: Baseline, monthly, and end of treatment, total of 4 months ] Participants will use the Dermatology Life Quality Index survey which measures how much their skin problems affect their life. Patients with a lifetime history of psychosis will be excluded. Trial protocol: FR Ongoing. Because of this, there have been studies exploring alternative isotretinoin dosing regimens including microdose, lower daily dose regimens 0. Psychiatric Disorders: Accutane may cause depression, psychosis and rarely, suicidal ideation, suicide attempts and suicide. Discovery and Pre-Market Approval : Perhaps the biggest challenge in chronicling Accutane has been to decipher the early history of the drug.

Study record managers: refer to the Data Element Definitions if submitting registration or results information. In current Dermatology practice, options for moderate acne vulgaris remain limited.

Moderate acne is clinically defined as acne that has not responded to at least three months of topical therapy and is not severe enough for initial treatment with a conventional course of isotretinoin formerly known as Accutane. The mainstay of treatment for moderate acne remains long courses of oral antibiotics, mainly tetracyclines doxycycline, minocycline and occasionally trimethoprim-sulfamethoxazole.

Males with moderate acne, in particular, are especially limited in their treatment options as they are not eligible for hormonal management spironolactone, oral contraceptive pills like their female counterparts. Additionally, even for those regardless of gender who may eventually qualify for a traditional isotretinoin course, many insurance companies first require failure to respond to at least three months of oral antibiotics.

Nagler et. Because of this, there is a significant need for more research on alternative treatment options for moderate acne. Once weekly isotretinoin dosing has the potential to significantly improve moderate acne with good patient satisfaction and safety profile; however, no study findings on this treatment option have been published to date.

The efficacy of isotretinoin, an oral vitamin A derivative, for treatment of acne has been well established. The traditional treatment course for severe acne consists of once to twice daily dosing 0. Though efficacious, there are numerous reported side-effects due to achieving the cumulative dose rapidly by once to twice daily dosing, such as severe dry skin, lips, and eyes, as well as liver enzyme and lipid abnormalities.

Because of this, there have been studies exploring alternative isotretinoin dosing regimens including microdose, lower daily dose regimens 0. Those who also analyzed adverse effect rates with alternative isotretinoin dosing found that these were either rarely observed or similar to conventional dosing. Interestingly, rates of acne recurrence between alternative isotretinoin dosing and conventional dosing were similar at follow-up,6,7,9 despite a much older study from that found otherwise.

Secondary endpoints include patient satisfaction and adverse effects. Participants are eligible for the study if their score is 3 or higher. An improvement in their visible acne is a score of 2, 1, or 0 at the end of the 4 months of treatment.

Secondary Outcome Measures : Number of Participants With a Change in Quality of Life [ Time Frame: Baseline, monthly, and end of treatment, total of 4 months ] Participants will use the Dermatology Life Quality Index survey which measures how much their skin problems affect their life.

The higher the score the more their skin impacts their day to day activities. An improvement in their quality of life is a lower score at 4 months compared to baseline score. Number of Side Effects Reported at the End of 4 Months [ Time Frame: through study completion, an average of 4 months ] Participants will fill out a survey regarding nonserious and serious adverse events. Talk with your doctor and family members or friends about deciding to join a study.

To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

We're building a better ClinicalTrials. Check it out and tell us what you think! Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information. Search for terms. Save this study. Warning You have reached the maximum number of saved studies Weekly Isotretinoin Therapy Study WIT The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.

Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Results First Posted : May 9, Last Update Posted : May 9, Study Description.

The mainstay of treatment for moderate acne remains long courses of oral antibiotics despite emerging antibiotic resistance. The efficacy of daily to twice daily dosed isotretinoin, an oral vitamin A derivative, for treatment of severe acne has been well established.

The purpose of this study is to determine if once weekly dosed isotretinoin is effective for the treatment of patients with moderate acne. Additionally, the study aims to evaluate patient satisfaction and identify any adverse effects on this alternative dosing regimen.

Detailed Description:. Drug Information available for: Isotretinoin. FDA Resources. Arms and Interventions. Outcome Measures. Participants will fill out a survey regarding nonserious and serious adverse events. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials. More Information. The use of oral antibiotics before isotretinoin therapy in patients with acne. J Am Acad Dermatol. Epub Oct Antibiotic stewardship in dermatology: limiting antibiotic use in acne. Eur J Dermatol. Bowe WP.

Antibiotic resistance and acne: where we stand and what the future holds. J Drugs Dermatol. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol. Low-dose schema of isotretinoin in acne vulgaris.

Int J Clin Pharmacol Res. Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study. Epub May Low-dose isotretinoin in the treatment of acne vulgaris. Kotori MG. Med Arch. Epub Feb Isotretinoin 5 mg daily for low-grade adult acne vulgaris--a placebo-controlled, randomized double-blind study. J Eur Acad Dermatol Venereol. Epub Apr Efficacy of fixed low-dose isotretinoin 20 mg, alternate days with topical clindamycin gel in moderately severe acne vulgaris.

Epub Jan 9. Treatment of acne with intermittent and conventional isotretinoin: a randomized, controlled multicenter study. Arch Dermatol Res. Epub Aug Treatment of acne with intermittent isotretinoin. Kaymak Y, Ilter N. The effectiveness of intermittent isotretinoin treatment in mild or moderate acne. Isotretinoin therapy for acne: results of a multicenter dose-response study. National Library of Medicine U.

National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Acne Vulgaris. Drug: Isotretinoin.

Phase 1 Phase 2. Study Type :. Interventional Clinical Trial. Actual Enrollment :. The study member assessing change in acne using the Comprehensive Acne Severity Scale does not know the medication the participants are taking. Actual Study Start Date :.

Actual Primary Completion Date :. Actual Study Completion Date :. Drug: Isotretinoin Participants will be getting isotretinoin



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