Letter to OLAF European Commission

Mr. Nicolas Ilett
Director General
OLAF
European Commission
B-1049 Brussels
BELGIUM

28 October 2010

Dear Director General,
Because it has not been possible over the last thirty years to obtain approval for my preparation Ukrain in Austria, despite all my efforts described below and the fulfilment of all legal requirements on my part, I have wondered about the reasons. Continual breaches of the law with infringement of procedural regulations in the matter of approval as well as not receiving equal treatment in violation of § 7 of Austrian Federal Constitutional Law have led me to the suspicion that corruption could be involved, which is why I am now turning to you in this matter. It is not I but cancer patients in Austria who have been disadvantaged because the health insurance institutions refuse to bear the expenses of treatment (Enclosure 51).
However, firstly I would firstly like to give you a brief outline of my preparation Ukrain.
After it was established in vitro and in vivo that Ukrain is effective against cancer and at the same time is 300 times less toxic than its starting substances (Enclosure 1) I applied for a patent at the Austrian Patent Office on 19 December 1975 (Enclosure 2).
In a 1976 study experts at the Federal Institute of Experimental Pharmacology and Balneology (Bundesstaatlichen Anstalt für experimentell-pharmakologische und balneologische Untersuchungen) in Vienna, Austria demonstrated that normal liver cells and Ehrlich tumour ascites cells demonstrate different oxygen consumption after incubation with Ukrain – after an initial increase the oxygen consumption of cancer cells falls to zero, which leads to the death of cancer cells, whereas the oxygen consumption of normal cells returns to normal and the cells remain undamaged (Enclosure 3). These were the first indications of the selective effect of Ukrain against cancer cells. Well-known universities and research institutes such as Rochester University (USA) (Enclosure 4), The University of Tübingen (Germany) (Enclosure 5) and the University of Mexico (Mexico) (Enclosure 6) among others have provided convincing evidence for the selective effect of Ukrain.
It has always been the greatest wish of cancer researchers to find a medicament that has a selective effect only against cancer cells. Despite the enormous efforts of numerous scientists around the world this problem was regarded as insoluble.
The discovery of the selective effect of Ukrain against cancer cells was a great step forward in deciphering the occurrence of cancer. So far Ukrain has been tested on more than 100 cancer cell lines as well as on healthy cells. All cancer cell lines were killed but none of the healthy cell lines.
Ukrain was tested in comparative studies on 18 malignant and 12 normal cell lines under identical conditions (Enclosures 4-6). These experiments dispelled all doubt with regard to the selective effect of Ukrain. Numerous studies have proved that Ukrain is the first and only cancer medicament that is toxic for cancer cells but not for healthy cells. This also explains its good tolerability in clinical application.

Background to Approval
For the above-mentioned reasons I turned to the Federal Chancellor on 28 June 1976 with the request also to test my preparation clinically (Enclosure 7). This test has so far not taken place in Austria. In December 1976 I made an application for approval for the treatment of patients who had exhausted all other forms of therapy in accordance with the law in force at the time, Medical Specialities Order (Spezialitätenordnung) 1947 § 8 lines 2 and 3.
In spring 1978 the well-known Dr. Musianowycz from Paris began to use the preparation clinically. During 1978 I received the first results of a study in which 17 patients were included. Dr. Musianowycz pointed out to the Austrian authorities the necessity for further research with the preparation. The news of therapeutic successes spread among patients and doctors and I passed on the reports of therapy results to the Ministry of Health (Enclosure 52). At the end of 1978 I made an application for approval without the above-mentioned proviso. On 14 August 1981 the Minister of Health, Dr. Steyrer, informed me that I only needed a licence in order to be granted approval. When I submitted my licence all conditions for approval were thereby fulfilled. Despite this, approval has not been granted so far and my applications from 1976 and 1978 have not been dealt with by the authorities. Instead various obstacles have been set in my way (Enclosure 41), as outlined below.

Infringement of §7 Austrian Constitutional Law (Bundes-Verfassungsgesetz)
In 1993, that is 17 years after my application for Ukrain, 7 years after my supplementary application of 1986 and 5 years after all preconditions for approval, including production licence, had been fulfilled, the American company Bristol-Meyers Squibb was granted approval extremely quickly after making application for the highly-toxic product Taxol with the submission of only 17 case histories.  At that time the Ministry of Health had already been presented with more than 450 case histories of the application of Ukrain. Austria was the first country in the world in which Taxol was granted approval although Austria was not even its country of origin. However, Austria is the country of origin of Ukrain and despite this all proofs of efficacy have been ignored. It can be seen from the summary of product characteristics for Taxol that a whole series of tests were not carried out although this information is from August 1993 and contains the reason for approval.

Comparison Between the Approval Proceedings for Ukrain and Taxol
(Comparisons with the summary of product characteristics for Taxol – Enclosure 11 – are quoted in italics.)

TAXOL: “Comparative studies with other cytostatic drugs are not yet available.”
UKRAIN: Comparative studies with other cytostatic drugs – some of them randomised – are available, and in this comparison Ukrain proved itself to be an effective preparation without noteworthy side-effects. In a controlled randomised study with colon cancer the survival rate after 21 months in the group treated with Ukrain was 78.6%, in the patient group treated with the standard cytostatic drug 5-Fluorouracil and radiotherapy it was only 33.3% (Enclosure 8).

In a controlled randomised study of inoperable pancreatic cancer by Prof. Beger and colleagues at the Uniklinikum Ulm in Germany the survival rate in the Gemzitabine group after 6 months was 26%, in the Ukrain group 65% and 74% in the group with combined treatment. The longest survival period in the Gemzitabine group was 19 months, in the combination group it was 26 months and in the Ukrain group two patients were alive after 28 months (Enclosure 9).
The patients were monitored after the conclusion of the study and it was established that Ukrain was very well tolerated and all patients could also be treated as out-patients. Treatment with Ukrain brought a considerable prolongation of survival time in comparison to treatment with Gemzitabine alone. Combination therapy with Gemzitabine and Ukrain showed no advantage in comparison to monotherapy with Ukrain. The authors of the study conclude: “On the basis of this study we recommend the treatment of patients with advanced pancreatic cancer with Ukrain” (Enclosure 10).

TAXOL: “Application is strictly intravenous because with paravenous and intra-arterial application tissue irritation and damage to the vascular wall can occur…”  (Summary of product characteristics TAXOL®-concentrate for infusion, August 1993, approval number 1-28006, Enclosure 11).
In comparison Ukrain is an effective preparation without noteworthy side-effects. Its therapeutic index is 1250, which speaks for a high degree of safety. For this reason no cases of overdose with Ukrain are known. For conventional cytostatic drugs the therapeutic index is in the range of 1.4 – 1.8 (the therapeutic index is the ratio between the toxic and the therapeutic dose of a medicine).
On 25 April 2002 the supplementary application of 30 August 1986, which was  most recently modified with regard to the relevant fields of application with the notification of 7 December 2000 as well as the application of 5 March 2001 for Ukrain as a medical speciality under the proviso “after standard therapy has failed,” was rejected by the Federal Minister of Social Security and the Generations (Enclosure 12) despite numerous proofs of its efficacy, safety and quality (Enclosure 15). There follow quotes from the notification which served as justification for the rejection of the supplementary application for the approval of Ukrain of 1986 (applicant Nowicky Pharma, a “one-man company”) and compare them with the summary of product characteristics for Taxol, a pharmaceutical concern’s preparation, which were used as the basis for its application for approval in 1993.

UKRAIN – Reason for rejection: “There is a lack of data on chronic toxicity with a sufficiently high dosage and for the question of a cancerogenic effect.”
TAXOL: “There have been no tests on the possible cancerogenic effect of Taxol. During in vitro and in vivo tests on mammal cell systems Taxol proved to be mutagenic…” In the same test Ukrain proved not to be mutagenic (Enclosure 13).

UKRAIN: “In Part IV there is a lack of reliable data on the mechanism of action, pharmacokinetics and interactions with other pharmaceutical products.” This statement was contrary to the record – see above.
TAXOL: “Distribution, metabolism and secretion of Paclitaxel in humans are not fully clarified… The effect of a kidney or liver deficiency on the secretion of Paclitaxel has not been examined…”

TAXOL: “The most frequent significant side-effect of Taxol was bone marrow depression. Neutropenia … appeared in 90% of patients, severe neutropenia appeared in 52% of patients… Serious cardiovascular incidents occurred in 1% of patients, namely ventricular tachycardia, AV block, syncope and hypotonia, which in one case led to death.“

UKRAIN: “The acute tolerability of the substance appears good” (Enclosure 12). However, because the authorities did not know to what the effect of Ukrain could be attributed the application for the approval of Ukrain for patients who had exhausted all other modes of therapy was rejected on the following grounds: “In Part III it is not ascertained whether the observed effects are to be attributed to the supposed complex, to free alkaloids or to free Thiotepa.” In doing so they completely overlooked the fact that Thiotepa is a highly toxic product which is nowadays hardly used. In contrast Ukrain is an effective preparation without noteworthy side-effects.
It can be seen from these quotes that two measures are used in the approval of medicines: a highly toxic medicament of a pharmaceutical concern is approved in the shortest time despite its doubtful effect, demonstrated on 17 patients, while at the same time the application for the approval of Ukrain of 30 August 1986, most recently modified with regard to the relevant fields of application on 7 December 2000, as well as the supplementary application of 5 March 2001 with the proviso “after standard therapy has failed” was rejected although Ukrain is an effective medicine without noteworthy side-effects which has been used with hundreds of patients and numerous randomised studies have been submitted to the ministry. Here it should be emphasised that the Federal Institute did not only did not only find fault with the lack of a placebo group but the number of 30 patients suggested by the study director was rejected as not significant. Why were only 17 patients accepted for Taxol?
With the rejection of these applications for approval the many patients who had exhausted all other forms of therapy were robbed of the chance of improving the quality of their lives or prolonging or even saving their lives because the health insurance institutions refuse to bear the costs of treatment. Thus only those patients who can afford to do so can benefit from Ukrain.

Unlawful obstruction tactics as a result of the infringement of procedural rules by ministry civil servants in the approval of the anticancer preparation Ukrain

In 1979 Austrian civil servants intervened at the Patent Office to prevent the patent being issued to me. This was neither their duty nor did they have any kind of right to do so. Despite this I obtained the patent in Austria in 1980 and have been issued with patents all over the world.
In 1983 Ukrain was presented for the first time at the 13th Congress of Chemotherapy in Vienna and the treatment with Ukrain of more than 100 patients who had exhausted all other forms of therapy was described (Enclosure 14). As a result many scientists and doctors concerned themselves with the preparation, tested it and used it. So far Ukrain has been tested by 260 scientists from 24 countries in 60 universities and research institutes. Further international congresses, scientific symposia and publications followed (265, of which more than 150 can be seen in PubMed) (Enclosure 15).

In 1983 a top Ministry of Health civil servant said, “I will have retired before Ukrain receives approval.” (Enclosure 16)

More and more doctors were becoming interested in Ukrain all the time. More than 250 doctors used the preparation for patients who had exhausted all other forms of therapy on the basis of § 12 AMG (today § 8 AMG). This was a totally legal procedure which improved the quality of life for these patients (Enclosure 17), prolonged their lives (Enclosure 18) and in some cases saved their lives (Enclosure 19). I received more and more reports of good therapeutic successes which I passed on to the Ministry of Health. On the basis of these results scientists and doctors requested the ministry to test Ukrain and at the same time called for prompt approval (Enclosure 20).

On 25 July 1986 the first decree (Enclosure 21) and on 25 February 1994 the second decree (Enclosure 22) about the prohibition of the use of Ukrain were issued. The Higher Administrative Court (Verfassungsgerichtshof) annulled both decrees on 28 November 1995 with the decision B 2295/95-10 (Enclosure 23).

On 28 June 1993 the penal order of the Magistrat der Stadt Wien MBA 6/7 – S 12032/92 was issued against Dr. W. Nowicky for infringement of §84 line 5 iVm §11 AMG, BGBl. No. 185/1983 (Enclosure 24). On 13 October 1993 the Independent Administrative Panel (Unabhängige Verwaltungssenat) Vienna annulled the penal order in accordance with §66 clause 4 of AVG 1991 and discontinued proceedings in accordance with §45 clause 1 line 2 VStG (Enclosure 25).

Doctors who were prescribing Ukrain to patients were persecuted with disciplinary procedures and penal charges by the authorities. (Enclosures 26, 27).
Although all proceedings were won by the unjustly accused, many of the doctors distanced themselves from Ukrain because they did not want difficulties with the authorities.

On 2 June 1995 my applications for approval of 27 July 1981, 12 September 1985 and 30 August 1986 were rejected with the decision GZ 2.921.726/7-II/C/16b/95 of the Federal Minister of Health and Consumer Protection (Enclosure 28). This decision was annulled on 26 February 1996 with the verdict Zl. 95/10/0124 of the Higher Administrative Court due to unlawfulness as a result of the infringement of procedural rules (Enclosure 29).  

In 1992 the health authorities demanded a randomised study.
On 23 June 1993 the Health Ministry’s Pharmaceutical Advisory Board approved the study plans for randomised studies with colorectal cancer and malignant melanomas as well as a study in accordance with § 42 Austrian Drugs Act (AMG) (Enclosure 30). For the clinical study of outpatients in accordance with §42 AMG various oncological diseases were to be treated with Ukrain as occur in the normal practice of town and country doctors. The analytical work in the draft of this study is brought into line with the normal possibilities of general practitioners and certain limitations such as of locations in the countryside particularly as it was to be a case of patients who had already been pretreated and were mostly in a progressive state of disease. Because, due to unlawful decrees, criminal charges and disciplinary procedures nobody was prepared to carry out such a study in Austria it was carried out at university hospitals in Ukraine in accordance with the submitted study plan. The results were presented to the ministry in 1995 and published in 1996 (Enclosure 8). The authorities did not accept these studies because they had not been carried out in Austria. They insisted on a study carried out in Austria.
In 1995 the Federal Ministry of Science and Research made efforts to organise a study in Austria.
On 8 May 1995 Univ.Doz. Dr. A. Reinthaller wrote to the Federal Ministry of Science and Research with regard to the opinion of the Ethics Commission of the Medical Faculty of the University of Vienna on “the clinical test of the use of Ukrain with recurrent cervix carcinoma”. Because the commission insisted on a randomised, placebo-controlled, double-blind study he regarded such conditions as ethically intolerable and therefore felt forced to retract his application for the appraisal of a clinical study of Ukrain (Enclosure 31).
Not only the Ethics Commission, but on 17 July 1995 the ministry also made a placebo-controlled study one of the most important conditions for the approval of Ukrain (Enclosure 32). The ethical intolerability of this demand is even shown by a quote from the book “Guidelines for Clinical Studies” (“Leitfaden für klinische Studien”): “no sensible person would have the idea of comparing cytostatic drugs with a placebo” (Enclosure 33).
A placebo-controlled study would have meant that one group of patients of more than 30 people would have received Ukrain and another group of more than 30 people would have received a common salt solution placebo (Enclosure 34).
No hospital was prepared to carry out such a study, not only in Austria but also in other countries. The ministry’s condition for the approval of Ukrain therefore remained unfulfilled.
A striking example is the discrediting of Prof. Dr. Beger of the University of Ulm, who had carried out a randomised study with Ukrain as palliative therapy in pancreatic cancer (Enclosures 35, 36).

Doctors call for approval
Some doctors who did not allow themselves to be intimidated by various harassment such as disciplinary procedures and penal charges continued to use Ukrain for patients who had exhausted all other forms of therapy in accordance with § 12 AMG. They obtained the medicament from pharmacies.
Obviously in order to prevent this, on 2 December 1996 the president of the Austrian Chamber of Pharmacists (Apothekerkammer) put in writing that “a list of pharmacies which stock this preparation is not available and because it is not approved by the Ministry of Health this preparation may not be distributed as a medical speciality by Nowicky Pharma.” (Enclosure 37) Today I wonder whether this was intended to put a stop to the good results of therapy which had been reported by doctors.
In January 1997 the ministry was asked for prompt approval by doctors who had treated patients in their surgeries in accordance with § 42 AMG who had exhausted other forms of therapy as per § 12 AMG following the authorisation from the Federal Ministry of Health, Sport and Consumer Protection of 23 June 1993 (Enclosure 39). They did so particularly to give the health insurance institutions the opportunity to take over the costs of therapy (Enclosures 39, 40, 41).
By March 2002 the ministry had not only been asked for prompt approval by numerous scientists and doctors. In addition, six well-known expert assessors who had been recommended to me by the ministry and who had drawn up pharmaceutical, pharmacological and preclinical and clinical reports on Ukrain produced evidence of efficacy, safety and quality (Enclosure 15).
In spite of this Ukrain was not approved. I therefore filed a complaint to the European Court of Human Rights on 28.3.2002. On 24.2.2005 the court found against the Republic of  Austria due to conduct contrary to administrative regulations in the case of approval for Ukrain (Enclosure 7).
On 25.4.2002 the negative decision was issued by the Federal Ministry of Social Security and the Generations GZ 921.726/13.VI/16/02 with regard to the supplementary applications for the approval of Ukrain of 30.8.1986, 7.12.2000 and 5.3.2001, which were made under the proviso “after the failure of standard therapy” (Enclosure 12).
By 2002 Ukrain had been the subject of 190 scientific publications (Enclosure 15) and had already been presented 209 times at specialist international congresses (Enclosure 53). Four special editions of a scientific journal had been dedicated to Ukrain (Enclosures 54, 55, 56, 57).
The following reliable conclusions about the mechanism of action of Ukrain were made at this time:
Ukrain has a selective effect against cancer cells but not against healthy cells (Enclosures 3, 4, 5, 6).
The preparation accumulates in cancer cells very soon after administration (Enclosures 9, 48, 49).
Ukrain selectively induces apoptosis in cancer cells by causing the cell cycle stop in the G2M-phase (Enclosures 4, 5).
It inhibits the polymerisation of tubulin (Enclosure 59).
Ukrain brings about tumour encapsulation, which facilitates the surgical removal of tumours (Enclosures 56, 57, 58).
Ukrain regenerates and modulates the immune system (Enclosures 60, 61).
As early as 1976 tests carried out at the Federal Institute of Experimental Pharmacology and Balneology provided the first indications for the selective effect of Ukrain against cancer cells. It was demonstrated in this study that normal liver cells and Ehrlich tumour ascites cells demonstrate different oxygen consumption after incubation with Ukrain – after an initial increase the oxygen consumption of cancer cells falls to zero, which leads to the death of cancer cells, whereas the oxygen consumption of healthy cells returns to normal and they remain undamaged (Enclosure 3).
At the same time a series of randomised and controlled clinical studies were carried out among others for pancreatic cancer (Enclosures 9, 10), colonic and rectal cancer (Enclosures 8, 54), prostate cancer (Enclosure 55) and breast cancer (Enclosures 56, 57, 58).
In view of this data it is incomprehensible why the application for approval for the treatment of patients who had exhausted all other forms of therapy was rejected by the authorities.

Two assessors for pharmacological and chemical data established that the suggested test methods guarantee the safety and quality of the product. Four assessors for preclinical and clinical data were in favour of approval along with numerous doctors and scientists. In view of this data the ministry had no possibility of rejecting the application for approval.
Suspicion arises that in order to have grounds for rejection the ministry commissioned a further two assessors – unusually in this situation – neither of whom is an expert in the field of oncology. For this reason I also rejected one of the assessors. The other assessor in the field of chemistry admitted that he had not read most of the documentation. This chemist recommended that Ukrain should not be granted approval although, as a chemist he had neither the competence nor the right to come to such a judgement.
The ministry repeatedly recommended me to withdraw my applications of 1976 for the treatment of patients who had exhausted all other modes of therapy and 1978 without this proviso and to make a new application. I continually refused to do so (Enclosure 62) and filed only supplementary applications. However, I also received a negative decision dated 25.4.2002 for a supplementary application for patients who had exhausted all other forms of therapy.
On 29.5.2009 a penal order was issued by the Magistrat der Stadt Wien, Magistratische Bezirk for the 4th and 5th districts against Dr. W. Nowicky, Zl. MBA 4/5 – S2454/08, for infringement of 1) § 63 clause 1 Austrian Medicines Act (AMG), BgBl. Nr. 185/1983 idgF, 2) § 7 clause 6 Medicines Plant Rules (Arzneimittelbetriebsordnung) 2005 (AMBO 2005) idF BGBl. II Nr. 479/2004, 3) § 3 clause 2 AMBO 2005, 4) § 33 clause 2 AMBO 2005 and 5) §2 Medicines Import Act 2002 (AWEG 2002) until 11.1.2008 idF BGBl. Nr. 41/2006 and from 12.1.2008 idF BGBl Nr. 35/2008 (Enclosure 42). An appeal was made against this penal order. On 6.9.2010 the penal order of the Magistrat der Stadt Wien, Magistratische Bezirk for the 4th and 5th districts of 28.5.2009 against Dr. W. Nowicky was annulled in all five points with the decision of the Independent Administrative Panel Vienna (Enclosure 45).
On 6.8.2009 a new ruling of the Federal Office of Safety in Health Care was issued (Enclosure 43). This ruling was contested on 17.9.2009 at the Administrative and Constitutional Courts.
On 17.6.2010 I filed a complaint to the European Court of Human Rights on account of this ruling which was accepted on 2.7.2010 under No. 34757/10 (Enclosure 44).
As you can see from the enclosed letter from my lawyer dated 15.9.2010 he can imagine that the ministry civil servants who judge Ukrain very unfavourably will again order an inspection of the company (Enclosure 46). Here I suspect that a reason is again being sought to press criminal charges.
Instead of taking up recommendations of well-reputed doctors and specialists – for example, Dr. Musianowycz already called for examination of the preparation in 1979 writing, “The product deserves further research and experimentation” – the whole energy of the civil servants is being used for senseless criminal charges against me as the inventor of the preparation and against doctors who use the preparation in accordance with §12 (now §8) AMG. Senseless because this costs the state a lot of time and tax revenue and I have in any case been able to refute or win all of them. Unfortunately I am forced to invest a great deal of time and energy in this struggle with the authorities which I could better use for the development of new preparations. I am convinced that the latter is in the interest of patients who certainly find the continual obstructive tactics incomprehensible.
Austria is the country of origin of my medicament which is why I filed the first application for approval here. Until now my application from 1976 has not been dealt with and Austria still continues to create difficulties in obtaining approval. In the meantime I have been granted approval in other countries such as Belarus, Ukraine, Georgia, Turkmenistan, Tajikistan, Azerbaijan, Mexico, the United Arab Emirates and Tunisia with the same documentation that I submitted to the Austrian authorities (Enclosure 47).
My application for Orphan Drug Status to the European approval authorities (EMEA) was rejected. At the session the Austrian expert witness Prof. Winkler, whose statement formed the basis for the negative Austrian decision, in my opinion was very committed to ensuring that the EMEA would reach a negative decision with obviously incorrect statements (that Ukrain has no selective effect). Here again it was seen that with the same documentation Ukrain received Orphan Drug Designation without a problem in the USA and Australia for the rare disease pancreatic cancer.
Today I received the letter dated 25.10.2010 from the Federal Ministry of Health (Enclosure 64), whose content I must refute because the statement contained within it does not correspond to the truth. Enclosed is also my reply to it (Enclosure 65).
My efforts to obtain the right guaranteed to me are not only without success but have also remained unanswered although I have also turned to the Minister of Justice (Enclosure 49) and the Minister of Health (Enclosure 48) as well as to my lawyer (Enclosure 50) in order to find support in this matter. Since I have exhausted all possibilities I am now turning to you because there are facts of this case which certainly require examination by external authorities since it is obvious that conduct has not always been in conformity with the law.
Since this is a matter of public interest I shall take the liberty of publishing this letter as well as your reply on the internet.
Best regards,

Dr. W. Nowicky