Orphan drugs: small changes can make a difference.

Exceptional Parents, as a rule publishes information, not opinion. Occasionally, though, a topic is so critical to you, our magazine's readers, and your families and loved ones, that we must make clear where we stand. One of those topics is orphan drugs (drugs with a patient population of fewer than 200,000). In a two-part series beginning here and continuing next month, a research team of Exceptional Parent; staff and advisors outlines: (1) the drug approval process; (2) the Orphan Drug Act and the tremendously positive impact this piece of legislation has :had since its enactment 15 years ago; (3) dietary, supplements and their relationship to orphan drugs; and (4) how you can best advocate on the issues involved.

Bringing a new drug to market

Congress has given the Food and Drug Administration (FDA), a division of the Department of Health and Human Services, the responsibility of validating the safety and effectiveness of new drugs as treatments for specific health conditions prior t:o their being marketed in the United States. The FDA, in turn, requires that developers seeking approval of new drugs provide the agency with enough information to support their validation. Here are the stages of the drag development process:

Discovery. Scientists at pharmaceutical companies, universities and research institutions search for new compounds that may affect the course of diseases or treat the symptoms of disease. Promising compounds or new mechanisms of action are patented (providing 20 years of exclusivity) to protect their formulations while research continues. It is important to note that naturally occurring compounds cannot be patented, specific usages only can be patented for these compounds.

Pre-clinical. Extensive toxicological tests and animal studies are conducted to determine whether the drug is likely to be safe and effective in humans. Applications for testing on humans (clinical trials) must be approved by the FDA and by review boards of the institutions where the trials will take place.

Phase I Clinical Tests. Safety studies are conducted on a small number of healthy volunteers. Potential side effects may be identified in humans to determine if the compound is safe enough for further testing.

Phase II Clinical Tests. Volunteers who have the targeted disease are tested to determine at what dosage the drug's effectiveness appears to be greatest with the fewest side effects.

Phase III Clinical Tests. Trials in clinics or hospitals are conducted to determine the drug's effectiveness measured against a control group. Only products with a statistically significant effectiveness versus this control group are generally considered for marketing approval by the FDA

FDA Review. If data from all of the tests prove the compound's safety and efficacy, the drug developer submits all the results and files a New Drug Application (NDA) with the FDA. The FDA may request additional documentation, more extensive trials, or other support for the NDA.

FDA Approval. If the FDA concurs with the lest data, it will approve the drug along with the official labeling information submitted by the drug developer.

Post-Marketing Surveillance. After approval and distribution for sale, the manufacturer, FDA and health care professionals continue to monitor the drug's safety and efficacy when used in the larger general population. Sometimes a manufacturer voluntarily enrolls early users in Phase IV trials to formalize the monitoring process and help address any specific questions that the FDA might have, e.g. long term use.

As you can imagine, the drug development process can be long, arduous, and expensive.

* Of 5,000 compounds originally screened for their potential, only about 250 will be tested in the laboratory. Of those 250, just five will be eligible for Phase I trials and only one compound, or 0.02 percent of the original group, will ultimately be approved by the FDA.

* Table 1 displays the enormous growth in costs that pharmaceutical manufacturers assert is required to develop a new drug: from $54 million in 1976 to $500 million in 1997, an increase of more than 825 percent in 20 years.

[TABULAR DATA 1 NOT REPRODUCIBLE IN ASCII]

* Table 2 illustrates the time that the pharmaceutical industry claims is needed for drug development; the total process can now take more than 15 years, almost twice as long as it took in the 1960s.

[TABULAR DATA 2 NOT REPRODUCIBLE IN ASCII]

Several factors enable drug developers to achieve a return on their investment and thus create an incentive to continue Research and Development (R&D) activities. The first is patent protection, which prohibits the sale of identical products by other manufacturers for 20 years from the date of patent issue. Depending on when in the development continuum the product was patented, and how long the approval process takes, the manufacturer will have a few years of protection before the product can be copied and sold in the market. Another important factor is marketing exclusivity. This can range from 3 to 10 years, depending on the nature of the product, and guarantees the manufacturer that the FDA will not approve NDAs for competitive products during the exclusivity period.

Orphan drugs

There are more than 5,000 rare disorders that together affect as many as 20 million Americans, but individually may have an impact on as few as several hundred people. To those coping with a rare disorder, its existence alone warrants research to find treatments, if not cures. To pharmaceutical manufacturers, such limited markets severely restrict a company's ability to recover its initial investment for drug development. Therefore, achieving a return on investment may be almost impossible. In 1983, Congress enacted the Orphan Drug Act to provide incentives for companies to develop therapies that would otherwise not be commercially viable, serving populations of under 200,000 patients in the United States. Since then, the FDA has approved 170 orphan drugs and has designated approximately 850 as orphan drugs with about 680 that are currently experimental.

The most important incentive the Orphan Drug Act provides is a seven-year window of marketing exclusivity for a new orphan drug once it has FDA approval. Exclusivity offers developers of orphan drugs legal protection against introduction of an identical competing product :for the same disease. This protection reassures investors that there will be at least a chance for a return on investment and makes niche markets more attractive. If a competitor wants to get on the market with a similar drug, that competitor must go through all of the preclinical and clinical testing to prove that the drug is not only safe and effective, but is also "clinically superior" to the first orphan drug.

The second incentive was a tax credit, equal to 50 percent of qualified expenditures, for human clinical trials. These benefits were significantly limited, however, permitting. credit to be used only in those years when the expenditures were made and the company had taxable income. Smaller companies, especially, were often unable to make use of potential tax credits because they usually did not have enough profit to utilize the tax credit. This portion of the legislation was permitted to expire at the end of 1994. In 1997, Congress finally made orphan drug tax credits permanent and included a provision that allows companies to carry the credits back or forward and use them in a year when the company is profitable, This was a positive step. However, one further small change can really make a big difference.

Exceptional Parent believes that perhaps it is now time for Congress to enact legislation to extend the period of marketing exclusivity for orphan drugs from seven years to ten or twelve years. This would provide companies with sufficient time and incentive to continue to invest in development of new orphan drugs. Therefore, Exceptional Parent suggests you contact your senators and representatives, and others who have a particular interest in health care legislation, to demonstrate your support of such changes (see Leaders in Congress on Health Care).

Another benefit to both consumers and drug developers is that typically, the FDA approves orphan drugs much more quickly than drugs for larger patient populations. Fewer data are usually needed to support the NDA, since the clinical trials are often done in smaller patient groups. While the agency still requires a developer to prove the safety and efficacy of the new compound, the investments of time and money may be significantly smaller than those for a drug aimed at a large patient population.

Three families, three experiences

The successes of orphan drugs, and the potential for turning some dietary supplements into orphan drugs, are illustrated by three families whose children are on this month's cover of Exceptional Parent: the Hackers, the Gaines, and the Morgans.

At 18-months old, Brielle Hacker weighed only 14 pounds. She was too weak to smile, roll over, crawl, walk, talk or eat solid foods. Brielle was diagnosed with a life-threatening metabolic condition called mitochondrial myopathy. Her mitochondria (the powerhouses of the cells) were unable to properly mm food into the energy that powers growth and activity. Brielle was also diagnosed with a secondary condition called carnitine deficiency. Carnitine, produced by the body and found in red meats and dairy foods, helps turn digested food into energy, and also helps expel waste products from the body. (See the EXCEPTIONAL PARENT issues of June, July and August 1997 dealing with mitochondrial and metabolic disorders.)

To replenish Brielle's carnitine level, Dr. Jess Thoene, professor and division chief of the Department of Pediatrics Biochemical Genetics at the University of Michigan, placed her on a prescription drug called Carnitor [R] (levocarnitine). In addition, her diet was enhanced by PediaSure [R], a vitamin enriched, high fat pediatric formula. Brielle's mother, Julie, saw noticeable differences in her daughter's energy level after introducing these products, and desperately continued to seek additional treatment therapies.

After talking to parents of other children with mitochondrial disorders, and searching the Internet, Julie learned of an alternative vitamin therapy called Coenzyme Q 10 (CoQ10) or ubiquinone. Co-Q10 is a vitamin-like nutrient found widely in foods and also produced by the body. An essential cofactor in the mitochondrial electron transport chain, Co-Q10 is a naturally occurring antioxidant nutrient: that slows down free radical formation in biological systems. It works like a shuttle in the mitochondria, moving around in a circle picking up and depositing electrons believed to be involved in cellular energy production. Because Co-Q10 is essential for cellular energy production, and because people are composed of billions of cells, ii is believed to be ultimately responsible for energy levels.

Julie consulted Dr. Thoene before starting Brielle on the CoEnzyme Q 10. He was concerned about using dietary supplements because they are not regulated as drugs, While that may be fine for the general public, patients need to know that the products they use to deal with specific health conditions are manufactured with the highest quality and research to back their use.

Dr. Thoene acknowledged that there could be some medical benefits for Bridle by taking the Co-Q10; however, there were also medical risks in giving her a product with contents that had no FDA standards to meet. There simply was no way to assure bio-equivalency and potency as there are many brands of Co-Q10 on the market in health food products stores. Dr. Thoene would prefer that Bridle, or any patient, use Co-Q10 that was clinically tested, researched and manufactured to meet the same rigorous standards as those mandated by the FDA for a prescription product. While Dr. Thoene warned Julie about these issues, he also recognized that Bridle had a life-threatening condition with few treatment options. Ultimately, Dr. Thoene stated that he supported Julie in whatever decision she made for Bridle, but he felt that she must review the risks and the benefits for her daughter of using a dietary supplement in a therapeutic manner.

After weighing her options, Julie decided to place Brielle on Co-Q10. "I knew was grasping for straws, but at that point in Brielle's life, I was glad just to have a straw to grasp. I was fearful of Brielle's reaction to CoQ, but I also felt that I had to try it if it might improve her condition." Julie then kept a daily journal of the dosage, time given, and any changes in Brielle's condition. Incredibly, after about three weeks, Brielle began to show signs of improvement. She began to smile, roll over, and sit independently, while showing no adverse reactions to the supplement.

At about the same time the Hackers were experimenting with CoEnzyme Q10, John and Angela Gaine of Goshen, New York, were ready to try Co-Q10 for their two-year-old son Daniel. The Gaines first became concerned about Daniel when he did not seem to be developing as quickly as had his older brother, Matthew. At five months of age, Daniel had no weight-bearing ability, and could not hold his head up on his own. After many misdiagnoses, a complete metabolic workup and a muscle biopsy, an electrocardiogram revealed that Daniel's heart, like his other muscles, was weak, and that his condition might involve primary carnitine deficiency. At one year of age, Daniel was immediately placed on Carnitor [R], and within 48 hours he began to hold his head up and bear weight on his legs. The Gaines were thrilled with his progress, but they also wondered if there were other products that would help also increase Daniel's energy level.

After consulting with a specialist in metabolic disorders, the Gaines were advised that many parents had seen dramatic differences in muscle strength and energy levels after placing their children on CoEnzyme Q 10. John and Angela scoured the Internet to educate themselves about Co-Q10 and then decided to see if it would help Daniel. "We had done our homework, and were desperate to take a chance flint this product might make Daniel stronger," explained the Gaines. After three days on Co-Q10, Daniel's health suddenly deteriorated. He became nauseated and lethargic, and developed a high fever. His parents immediately took Daniel off the Co-Q10, and the negative symptoms diminished.

Meanwhile, across the country in Concord, California, Kevin and Lynnie Morgan wrestled with their own concerns about placing their daughter, Amy, on CoEnzyme Q 10. Amy, then 19, was diagnosed with mitochondrial encephalopathy, a form of mitochondrial disorder that caused Amy to have muscle weakness, seizures, and dementia. The Morgans also investigated Co-Q10 and decided not to take the chance of experimenting with a dietary supplement. They had experienced a negative reaction in the past when Amy had been on a prescribed medication to control her seizures and, although it did control the secure activity, it caused her dementia to worsen.

The Morgans believed then that they had made an informed decision because they were giving their daughter a product that had been approved by the FDA: they knew Amy might experience side effects. "It was one thing to take a chance on a prescription drug where the possible side effects were known; however, it was not worth taking a chance on an over the counter (OTC) product on which little research or testing had been completed. We were torn, because we wanted to try anything that might help Amy, but we did not want to take a chance on her life."

These three families experienced three different results with Co-Q10 as they searched for potential treatments. It is unfortunate that the current: system is a disincentive to further research on Co-Q10 since it apparently cart provide benefits in some patients. Further research, however, costs money. If the system could be modified to provide for a more expanded period of marketing exclusivity a company willing to invest in research on Co-Q10 would perhaps be able to justify the level of investment required. It would ultimately result in a inning scenario for all concerned. Sometimes little things mean a lot, and small changes make a big difference!

Sample Orphan Drugs

Trade Name         Generic Name          Orphan Indication

Acthrel            corticorelin          For use in differentiating
                   ovine triflutate      pituitary and ectopic
                                         production of ACTH in
                                         patients with
                                         ACTH-dependent
                                         Cushings Syndrome

Agrylin            anagrelide            Treatment of essential
                                         thrombocythemia

Albenza            albendazole           Treatment of
                                         neurocysticercosis due to
                                         Taenia solium

Botox              botulinum             Treatment of blepharospasm
                   toxin type a          associated with dystonia in
                                         patients 12 years of age
                                         and above

Carnitor           levocarnitine         Treatment of genetic
                                         carnitine deficiency

Ceredase           alglucerase           Replacement therapy in
                   injection             patients with Gaucher's
                                         disease Type 1

Cordarone          amiodarone HCI        Acute treatment and
                                         prophylaxis of life-
                                         threatening ventricular
                                         tachycardia or ventricular
                                         fibrillation

Cystadane          betaine               Treatment of homocystinuria

Kogenate           antihemophilic        Prophylaxis and treatment
factor             (recombinant)         of bleeding in individuals
                                         with hemophilia A.

Lioresal           baclofen              Treatment of intractable
Intrathecal                              spasticity caused by spinal
                                         cord injury, multiple
                                         sclerosis, other spinal
                                         diseases

Lupron injection   leuprolide acetate    Treatment of central
Prolastin          alpha-1 -proteinase    precocious puberty
                   inhibitor (human)     Replacement therapy in the
                                         alpha-1 -proteinase
                                         inhibitor congenital
                                         deficiency state

Survanta           beractant             Prevention and treatment of
intratracheal                            neonatal respiratory
suspension                               distress syndrome.

TOBI               tobramycin            Treatment of
                   for inhalation        bronchopulmonary infections
                                         of Pseudomonas aeruginosa
                                         in cystic fibrosis patients

RELATED ARTICLE: Leaders in Congress on health Care

These representatives and senators have taken a particular interest in health care issues and orphan drugs over the years. It would be a good idea to share your thoughts with them and with your own representative and senators. There are many other members of Congress who have a keen interest in these issues.

U. S. Senators Sen. Bill Frist, MD (R-TN) Sen. Tom Harkin (D-IA) Sen. Orrin Hatch (R-UT) Sen. Jim Jeffords (R-VT) Sen. Edward Kennedy (D-MA)

U. S. Representatives Rep Michael Bilirakis (R-FL) Rep Tom Bliley (R-VA) Rep John Dingell (D-MI) Rep Frank Pallone (D-NJ) Rep Henry Waxman (D-CA)

Here are the addresses to write to them and to your Congresspeople:

Hon. United States Senate Washington, DC 20510

-OR-

Hon. -- U.S. House of Representatives Washington, DC 20515

Want to speak to someone in these members' offices? Don't know who your representative or senators area? Call 1 202 224 3121 or 1 202 225 3121 and give your home state and zip code to the operator, who will tell you who represents you in Congress.

Orphan drugs developed from natural substances, including dietary supplements, are rare, and that is the crux of the problem. In next month's issue, EXCEPTIONAL PARENT will explain the role of natural substances in the pharmacopeia, the legislation governing the marketing of dietary supplements, and how they tie in to the orphan drug development process.

Fern R. Potvin has many years of experience in health care issues and medical education. She is currently an independent publishing consultant.